AKT1 modulators for the treatment of cancer

Abstract

The disclosure herein provides methods for treating cancer using an AKT1 selective inhibitor. In some embodiments, the cancer comprises at least one mutation in the PI3K / AKT / PTEN signaling pathway. In some embodiments, the cancer is a PTEN loss of function cancer, a PTEN deficient cancer, a PTEN mutated cancer, a PTEN altered cancer, a PIK3CA activated cancer, or an AKT activated cancer. In some aspect, the present disclosure provides combinations useful for the treatment of cancers as disclosed herein.

Description

WSGR Docket No. 61402-725.601AKT1 MODULATORS FOR THE TREATMENT OF CANCER

[0001] This application claims the benefit of U. S. Provisional Application No. 63 / 789,946 filed April 16, 2025, the entirety of which is incorporated herein by reference.BACKGROUND OF THE INVENTION

[0002] The AKT or Protein Kinase B (PKB) family of serine / threonine protein kinases is comprised of 3 highly homologous members, AKT1, AKT2 and AKT3. The family of AKT proteins are involved in signal transduction pathways that regulate cellular processes including apoptosis, proliferation, differentiation, and metabolism. The AKT1 pathway is the most frequently dysregulated signaling pathways in human cancers. Enhanced activation of all the isoforms can be implicated in tumor development and progression, and has been demonstrated in breast, ovarian, pancreatic, and prostate cancers among others (Song et al., 2019). In cancer cells, AKT1 is involved in proliferation and growth, promoting tumor initiation, and suppressing apoptosis, whereas AKT2 regulates cytoskeleton dynamics, favoring local tissue invasion and metastasis. The role of AKT3 hyperactivation in cancer is hypothesized to be involved with possible stimulation of cell proliferation (Hinz et al., Cell Commun Signal 2019, 17(1), 154; Pascual et al., Ann. Oncol. 2019, 30(7), 1051-1060). Expression of these AKT family members is altered in many human malignant carcinomas including gastric, breast, prostate, ovarian, and pancreatic. AKT family members are rarely mutated however, the most common mutation is AKT1 E17K which has been reported in 6-8% of breast cancers, 2-6% of colorectal cancers, and in 6% of meningiomas, in humans (Yu et al., PLoS One 2015, 10 (10), No. e0140479). Thus, there is a need to develop new treatments for the modulation of AKT1 and mutants thereof.SUMMARY OF THE INVENTION

[0003] In some aspects, the present disclosure provides methods of treating cancer having at least one mutation in the PI3K / AKT / PTEN signaling pathway comprising, administering to a subject in need thereof an AKT1 selective inhibitor.

[0004] In some aspects, the present disclosure provides methods of treating cancer comprising: identifying a subject with at least one mutation in the PI3K / AKT / PTEN signaling pathway; and administering to the subject an AKT1 selective inhibitor.

[0005] In some aspects, the present disclosure provides methods of treating cancer comprising: selecting a subject with at least one mutation in the PI3K / AKT / PTEN signaling pathway; and administering to the subject an AKT1 selective inhibitor.WSGR Docket No. 61402-725.601

[0006] In some aspects, the present disclosure provides methods of treating cancer comprising: screening to identify a subject with at least one mutation in the PI3K / AKT / PTEN signaling pathway; and administering to the subject identified in the screen an AKT1 selective inhibitor.

[0007] In some aspects, the present disclosure provides methods of treating a PTEN loss of function cancer comprising, administering to a subject in need thereof an AKT1 selective inhibitor.

[0008] In some aspects, the present disclosure provides methods of treating cancer comprising: identifying a subject with a PTEN loss of function cancer; and administering to the subject an AKT1 selective inhibitor.

[0009] In some aspects, the present disclosure provides methods of treating cancer comprising: selecting a subject with a PTEN loss of function cancer; and administering to the subject an AKT1 selective inhibitor.

[0010] In some aspects, the present disclosure provides methods of treating cancer comprising: screening to identify a subject with a PTEN loss of function cancer; and administering to the subject identified in the screen an AKT1 selective inhibitor.

[0011] In some aspects, the present disclosure provides methods of treating a PTEN deficient cancer comprising, administering to a subject in need thereof an AKT1 selective inhibitor.

[0012] In some aspects, the present disclosure provides methods of treating cancer comprising: identifying a subject with a PTEN deficient cancer; and administering to the subject an AKT1 selective inhibitor.

[0013] In some aspects, the present disclosure provides methods of treating cancer comprising: selecting a subject with a PTEN deficient cancer; and administering to the subject an AKT1 selective inhibitor.

[0014] In some aspects, the present disclosure provides methods of treating cancer comprising: screening to identify a subject with a PTEN deficient cancer; and administering to the subject identified in the screen an AKT1 selective inhibitor.

[0015] In some aspects, the present disclosure provides methods of treating a PTEN altered cancer comprising, administering to a subject in need thereof an AKT1 selective inhibitor.

[0016] In some aspects, the present disclosure provides methods of treating cancer comprising: identifying a subject with a PTEN altered cancer; and administering to the subject an AKT1 selective inhibitor.

[0017] In some aspects, the present disclosure provides methods of treating cancer comprising: selecting a subject with a PTEN altered cancer; and administering to the subject an AKT1 selective inhibitor.WSGR Docket No. 61402-725.601

[0018] In some aspects, the present disclosure provides methods of treating cancer comprising: screening to identify a subject with a PTEN altered cancer; and administering to the subject identified in the screen an AKT1 selective inhibitor.

[0019] In some aspects, the present disclosure provides methods of treating a PTEN mutated cancer comprising, administering to a subject in need thereof an AKT1 selective inhibitor.

[0020] In some aspects, the present disclosure provides methods of treating cancer comprising: identifying a subject with a PTEN mutated cancer; and administering to the subject an AKT1 selective inhibitor.

[0021] In some aspects, the present disclosure provides methods of treating cancer comprising: selecting a subject with a PTEN mutated cancer; and administering to the subject an AKT1 selective inhibitor.

[0022] In some aspects, the present disclosure provides methods of treating cancer comprising: screening to identify a subject with a PTEN mutated cancer; and administering to the subject identified in the screen an AKT1 selective inhibitor.

[0023] In some aspects, the present disclosure provides methods of treating cancer comprising, administering to a subject in need thereof an AKT1 selective inhibitor, wherein the subject has a relapsed or refractory cancer after receiving at least one prior treatment.

[0024] In some aspects, the present disclosure provides methods of treating cancer comprising, administering to a subject in need thereof an AKT1 selective inhibitor, wherein the subject has been previously administered a selective estrogen receptor degrader (SERD).

[0025] In some aspects, the present disclosure provides methods of treating cancer comprising, administering to a subject in need thereof an AKT1 selective inhibitor, wherein the subject has been previously administered an aromatase inhibitor.

[0026] In some aspects, the present disclosure provides methods of treating cancer comprising, administering to a subject in need thereof an AKT1 selective inhibitor, wherein the subject has been previously administered a CDK4 / 6 inhibitor.

[0027] In some aspects, the present disclosure provides methods of treating cancer comprising, administering to a subject in need thereof an AKT1 selective inhibitor, wherein the subject has been previously administered an anti-androgen.

[0028] In some aspects, the present disclosure provides methods of treating cancer comprising, administering to a subject in need thereof an AKT1 selective inhibitor, wherein the subject has been previously administered a selective estrogen receptor degrader (SERD) and a CDK4 / 6 inhibitor.WSGR Docket No. 61402-725.601

[0029] In some aspects, the present disclosure provides methods of treating cancer comprising, administering to a subject in need thereof an AKT1 selective inhibitor, wherein the subject has been previously administered an aromatase inhibitor and a CDK4 / 6 inhibitor.

[0030] In some aspects, the present disclosure provides methods of treating cancer comprising, administering to a subject in need thereof an AKT1 selective inhibitor and a second agent selected from a CDK2 inhibitor, a CDK4 / 6 inhibitor, an aromatase inhibitor, an anti -androgen, an androgen synthesis inhibitor, an mTOR inhibitor, a PI3Ka inhibitor, a PI3Ka mutant inhibitor, a gonadotropin-releasing hormone (GnRH) agonist, a selective estrogen receptor modulator (SERM), and a selective estrogen receptor degrader (SERD).

[0031] In some aspects, the present disclosure provides methods of treating cancer having at least one mutation in the PI3K / AKT / PTEN signaling pathway comprising, administering to a subject in need thereof (S)-1-(4-((5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)piperidin-1-yl)prop-2-en-1-one or a pharmaceutically acceptable salt thereof.

[0032] In some aspects, the present disclosure provides methods of treating cancer comprising: identifying a subject with at least one mutation in the PI3K / AKT / PTEN signaling pathway; and administering to the subject (S)-1-(4-((5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)piperidin-1-yl)prop-2-en-1-one or a pharmaceutically acceptable salt thereof.

[0033] In some aspects, the present disclosure provides methods of treating cancer comprising: selecting a subject with at least one mutation in the PI3K / AKT / PTEN signaling pathway; and administering to the subject (S)-1-(4-((5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)piperidin-1-yl)prop-2-en-1-one or a pharmaceutically acceptable salt thereof.

[0034] In some aspects, the present disclosure provides methods of treating cancer comprising: screening to identify a subject with at least one mutation in the PI3K / AKT / PTEN signaling pathway; and administering to the subject identified in the screen (S)-l-(4-((5-(2-(2-aminopyridin-3-yl)-5-(lH-pyrazol-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-lH-inden-l-yl)amino)piperidin-l-yl)prop-2-en-l-one or a pharmaceutically acceptable salt thereof.

[0035] In some aspects, the present disclosure provides methods of treating a PTEN mutated cancer comprising, administering to a subject in need thereof (S)-l-(4-((5-(2-(2-aminopyridin-3-yl)-5-(lH-pyrazol-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-lH-inden-l-yl)amino)piperidin-l-yl)prop-2-en-l-one or a pharmaceutically acceptable salt thereof.

[0036] In some aspects, the present disclosure provides methods of treating cancer comprising: identifying a subject with a PTEN mutated cancer; and administering to the subject (S)-l-(4-((5-WSGR Docket No. 61402-725.601(2-(2-aminopyridin-3-yl)-5-(lH-pyrazol-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-lH-inden- l-yl)amino)piperidin-l-yl)prop-2-en-l -one or a pharmaceutically acceptable salt thereof.

[0037] In some aspects, the present disclosure provides methods of treating cancer comprising: selecting a subject with a PTEN mutated cancer; and administering to the subject (S)-l-(4-((5-(2-(2-aminopyridin-3-yl)-5-(lH-pyrazol-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-lH-inden- l-yl)amino)piperidin-l-yl)prop-2-en-l -one or a pharmaceutically acceptable salt thereof.

[0038] In some aspects, the present disclosure provides methods of treating cancer comprising: screening to identify a subject with a PTEN mutated cancer; and administering to the subject identified in the screen (S)-1-(4-((5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)piperidin-1-yl)prop-2-en-1-one or a pharmaceutically acceptable salt thereof.

[0039] In some aspects, the present disclosure provides methods of treating a PTEN loss of function cancer comprising, administering to a subject in need thereof (S)-l-(4-((5-(2-(2-aminopyridin-3-yl)-5-(lH-pyrazol-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-lH-inden-l-yl)amino)piperidin-l-yl)prop-2-en-l-one or a pharmaceutically acceptable salt thereof.

[0040] In some aspects, the present disclosure provides methods of treating cancer comprising: identifying a subject with a PTEN loss of function cancer; and administering to the subject (S)-l-(4-((5-(2-(2-aminopyridin-3-yl)-5-(lH-pyrazol-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-lH-inden-l-yl)amino)piperidin-l-yl)prop-2-en-l-one or a pharmaceutically acceptable salt thereof.

[0041] In some aspects, the present disclosure provides methods of treating cancer comprising: selecting a subject with a PTEN loss of function cancer; and administering to the subject (S)-l-(4-((5-(2-(2-aminopyridin-3-yl)-5-(lH-pyrazol-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro- lH-inden-l-yl)amino)piperidin-l-yl)prop-2-en-l -one or a pharmaceutically acceptable salt thereof.

[0042] In some aspects, the present disclosure provides methods of treating cancer comprising: screening to identify a subject with a PTEN loss of function cancer; and administering to the subject identified in the screen (S)-1-(4-((5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)piperidin-1-yl)prop-2-en-1-one or a pharmaceutically acceptable salt thereof.

[0043] In some aspects, the present disclosure provides methods of treating a PTEN deficient cancer comprising, administering to a subject in need thereof (S)-l-(4-((5-(2-(2-aminopyridin-3-yl)-5-(lH-pyrazol-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-lH-inden-l-yl)amino)piperidin-l-yl)prop-2-en-l-one or a pharmaceutically acceptable salt thereof.WSGR Docket No. 61402-725.601

[0044] In some aspects, the present disclosure provides methods of treating cancer comprising: identifying a subject with a PTEN deficient cancer; and administering to the subject (S)-l-(4-((5-(2-(2-aminopyridin-3-yl)-5-(lH-pyrazol-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-lH-inden-l-yl)amino)piperidin-l-yl)prop-2-en-l-one or a pharmaceutically acceptable salt thereof.

[0045] In some aspects, the present disclosure provides methods of treating cancer comprising: selecting a subject with a PTEN deficient cancer; and administering to the subject (S)-l-(4-((5-(2-(2-aminopyridin-3-yl)-5-(lH-pyrazol-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-lH-inden- l-yl)amino)piperidin-l-yl)prop-2-en-l -one or a pharmaceutically acceptable salt thereof.

[0046] In some aspects, the present disclosure provides methods of treating cancer comprising: screening to identify a subject with a PTEN deficient cancer; and administering to the subject identified in the screen (S)-1-(4-((5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)piperidin-1-yl)prop-2-en-1-one or a pharmaceutically acceptable salt thereof.

[0047] In some aspects, the present disclosure provides methods of treating a PTEN altered cancer comprising, administering to a subject in need thereof (S)-l-(4-((5-(2-(2-aminopyridin-3-yl)-5-(lH-pyrazol-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-lH-inden-l-yl)amino)piperidin-l-yl)prop-2-en-l-one or a pharmaceutically acceptable salt thereof.

[0048] In some aspects, the present disclosure provides methods of treating cancer comprising: identifying a subject with a PTEN altered cancer; and administering to the subject (S)-l-(4-((5-(2-(2-aminopyridin-3-yl)-5-(lH-pyrazol-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-lH-inden- l-yl)amino)piperidin-l-yl)prop-2-en-l -one or a pharmaceutically acceptable salt thereof.

[0049] In some aspects, the present disclosure provides methods of treating cancer comprising: selecting a subject with a PTEN altered cancer; and administering to the subject (S)-l-(4-((5-(2-(2-aminopyridin-3-yl)-5-(lH-pyrazol-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-lH-inden-l-yl)amino)piperidin-l-yl)prop-2-en-l-one or a pharmaceutically acceptable salt thereof.

[0050] In some aspects, the present disclosure provides methods of treating cancer comprising: screening to identify a subject with a PTEN altered cancer; and administering to the subject identified in the screen (S)-1-(4-((5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)piperidin-1-yl)prop-2-en-1-one or a pharmaceutically acceptable salt thereof.

[0051] In some aspects, the present disclosure provides methods of treating a PIK3CA activated cancer comprising, administering to a subject in need thereof (S)-l-(4-((5-(2-(2-aminopyridin-3-yl)-5-(lH-pyrazol-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-lH-inden-l-yl)amino)piperidin-l-yl)prop-2-en-l-one or a pharmaceutically acceptable salt thereof.WSGR Docket No. 61402-725.601

[0052] In some aspects, the present disclosure provides methods of treating cancer comprising: identifying a subject with a PIK3CA activated cancer; and administering to the subject (S)-l-(4-((5-(2-(2-aminopyridin-3-yl)-5-(lH-pyrazol-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-lH-inden-l-yl)amino)piperidin-l-yl)prop-2-en-l-one or a pharmaceutically acceptable salt thereof.

[0053] In some aspects, the present disclosure provides methods of treating cancer comprising: selecting a subject with a PIK3CA activated cancer; and administering to the subject (S)-l-(4-((5-(2-(2-aminopyridin-3-yl)-5-(lH-pyrazol-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-lH-inden-l-yl)amino)piperidin-l-yl)prop-2-en-l-one or a pharmaceutically acceptable salt thereof.

[0054] In some aspects, the present disclosure provides methods of treating cancer comprising: screening to identify a subject with a PIK3CA activated cancer; and administering to the subject identified in the screen (S)-1-(4-((5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)piperidin-1-yl)prop-2-en-1-one or a pharmaceutically acceptable salt thereof.

[0055] In some aspects, the present disclosure provides methods of treating a AKT activated cancer comprising, administering to a subject in need thereof (S)-l-(4-((5-(2-(2-aminopyridin-3-yl)-5-(lH-pyrazol-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-lH-inden-l-yl)amino)piperidin-l-yl)prop-2-en-l-one or a pharmaceutically acceptable salt thereof.

[0056] In some aspects, the present disclosure provides methods of treating cancer comprising: identifying a subject with a AKT activated cancer; and administering to the subject (S)-l-(4-((5-(2-(2-aminopyridin-3-yl)-5-(lH-pyrazol-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-lH-inden- l-yl)amino)piperidin-l-yl)prop-2-en-l -one or a pharmaceutically acceptable salt thereof.

[0057] In some aspects, the present disclosure provides methods of treating cancer comprising: selecting a subject with a AKT activated cancer; and administering to the subject (S)-l-(4-((5-(2-(2-aminopyridin-3-yl)-5-(lH-pyrazol-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-lH-inden- l-yl)amino)piperidin-l-yl)prop-2-en-l -one or a pharmaceutically acceptable salt thereof.

[0058] In some aspects, the present disclosure provides methods of treating cancer comprising: screening to identify a subject with a AKT activated cancer; and administering to the subject identified in the screen (S)-1-(4-((5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)piperidin-1-yl)prop-2-en-1-one or a pharmaceutically acceptable salt thereof.

[0059] In some aspects, the present disclosure provides methods of treating cancer comprising, administering to a subject in need thereof (S)-l-(4-((5-(2-(2-aminopyridin-3-yl)-5-(lH-pyrazol-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-lH-inden-l-yl)amino)piperidin-l-yl)prop-2-WSGR Docket No. 61402-725.601en-l-one or a pharmaceutically acceptable salt thereof, wherein the subject has a relapsed or refractory cancer after receiving at least one prior treatment.

[0060] In some aspects, the present disclosure provides methods of treating cancer comprising, administering to a subject in need thereof (S)-l-(4-((5-(2-(2-aminopyridin-3-yl)-5-(lH-pyrazol-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-lH-inden-l-yl)amino)piperidin-l-yl)prop-2-en-l-one or a pharmaceutically acceptable salt thereof, wherein the subject has been previously administered a SERD.

[0061] In some aspects, the present disclosure provides methods of treating cancer comprising, administering to a subject in need thereof (S)-l-(4-((5-(2-(2-aminopyridin-3-yl)-5-(lH-pyrazol-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-lH-inden-l-yl)amino)piperidin-l-yl)prop-2-en-l-one or a pharmaceutically acceptable salt thereof, wherein the subject has been previously administered an aromatase inhibitor.

[0062] In some aspects, the present disclosure provides methods of treating cancer comprising, administering to a subject in need thereof (S)-l-(4-((5-(2-(2-aminopyridin-3-yl)-5-(lH-pyrazol-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-lH-inden-l-yl)amino)piperidin-l-yl)prop-2-en-l-one or a pharmaceutically acceptable salt thereof, wherein the subject has been previously administered a CDK4 / 6 inhibitor.

[0063] In some aspects, the present disclosure provides methods of treating cancer comprising, administering to a subject in need thereof (S)-l-(4-((5-(2-(2-aminopyridin-3-yl)-5-(lH-pyrazol-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-lH-inden-l-yl)amino)piperidin-l-yl)prop-2-en-l-one or a pharmaceutically acceptable salt thereof, wherein the subject has been previously administered an anti -androgen.

[0064] In some aspects, the present disclosure provides methods of treating cancer comprising, administering to a subject in need thereof (S)-l-(4-((5-(2-(2-aminopyridin-3-yl)-5-(lH-pyrazol-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-lH-inden-l-yl)amino)piperidin-l-yl)prop-2-en-l-one or a pharmaceutically acceptable salt thereof, wherein the subject has been previously administered a SERD and a CDK4 / 6 inhibitor.

[0065] In some aspects, the present disclosure provides methods of treating cancer comprising, administering to a subject in need thereof (S)-l-(4-((5-(2-(2-aminopyridin-3-yl)-5-(lH-pyrazol-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-lH-inden-l-yl)amino)piperidin-l-yl)prop-2-en-l-one or a pharmaceutically acceptable salt thereof, wherein the subject has been previously administered an aromatase inhibitor and a CDK4 / 6 inhibitor.

[0066] In some aspects, the present disclosure provides methods of treating cancer comprising, administering to a subject in need thereof (S)-l-(4-((5-(2-(2-aminopyridin-3-yl)-5-(lH-pyrazol-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-lH-inden-l-yl)amino)piperidin-l-yl)prop-2-WSGR Docket No. 61402-725.601en-l-one or a pharmaceutically acceptable salt thereof, and a second agent selected from a CDK2 inhibitor, a CDK4 / 6 inhibitor, an aromatase inhibitor, an anti-androgen, an androgen synthesis inhibitor, an mTOR inhibitor, a PI3Ka inhibitor, a PI3Ka mutant inhibitor, a gonadotropin-releasing hormone (GnRH) agonist, a selective estrogen receptor modulator (SERM), and a selective estrogen receptor degrader (SERD).

[0067] In some embodiments, the subject has a relapsed cancer after receiving at least one prior treatment. In some embodiments, the subject has a refractory cancer after receiving at least one prior treatment.

[0068] In some embodiments, the at least one prior treatment is selected from surgery, radiation, and chemotherapy. In some embodiments, the chemotherapy is selected from a CDK4 / 6 inhibitor, an aromatase inhibitor, an anti-androgen, an androgen synthesis inhibitor, an mTOR inhibitor, a PI3Ka inhibitor, a PI3Ka mutant inhibitor, a gonadotropin-releasing hormone (GnRH) agonist, a selective estrogen receptor modulator (SERM), and a selective estrogen receptor degrader (SERD).

[0069] In some embodiments, the surgery is a complete resection or a partial resection.

[0070] In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is selected from breast cancer, kidney cancer, prostate cancer, head and neck cancer, gastric cancer, lung cancer, endometrial cancer, ovarian cancer, cervical cancer, esophageal cancer, and colon cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the breast cancer is ER+ / HER2- breast cancer. In some embodiments, the breast cancer is triple negative breast cancer.

[0071] In some embodiments, the cancer is kidney cancer. In some embodiments, the kidney cancer is renal cell carcinoma. In some embodiments, the cancer is prostate cancer. In some embodiments, the prostate cancer is castration resistant prostate cancer. In some embodiments, the cancer is head and neck cancer. In some embodiments, the head and neck cancer is head and neck squamous cell carcinoma. In some embodiments, the cancer is gastric cancer. In some embodiments, the cancer is lung cancer. In some embodiments, the lung cancer is squamous cell lung cancer. In some embodiments, the cancer is endometrial cancer. In some embodiments, the cancer is colon cancer. In some embodiments, the colon cancer is colorectal cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is cervical cancer. In some embodiments, the cancer is esophageal cancer.

[0072] In some embodiments, the esophageal cancer is squamous cell esophageal cancer.

[0073] In some embodiments, the subject is administered a second agent selected from a CDK2 inhibitor, a CDK4 / 6 inhibitor, an aromatase inhibitor, an anti -androgen, an androgen synthesis inhibitor, an mTOR inhibitor, a PI3Ka inhibitor, a PI3Ka mutant inhibitor, a gonadotropin-WSGR Docket No. 61402-725.601releasing hormone (GnRH) agonist, a selective estrogen receptor modulator (SERM), and a selective estrogen receptor degrader (SERD).

[0074] In some embodiments, the at least one mutation in the PI3K / AKT / PTEN signaling pathway is an insertion, a deletion, or a substitution at a residue. In some embodiments, the at least one mutation in the PI3K / AKT / PTEN signaling pathway is a PIK3CA mutation. In some embodiments, the PIK3CA mutation is at a residue selected from R88, R93, G106, K111, G118, N345, C420, E453, E542, E545, Q546, M1043, H1047, and G1049. In some embodiments, the PIK3CA mutation is at a residue selected from R38, R88, R93, G106, K111, G118, C124, K342, N345, C420, E453, E542, E545, Q546, M1043, H1047, and G1049. In some embodiments, the at least one mutation in the PI3K / AKT / PTEN signaling pathway is a AKT1 mutation. In some embodiments, the AKT1 mutation is at residue El 7. In some embodiments, the AKT1 mutation is E17K. In some embodiments, the at least one mutation in the PI3K / AKT / PTEN signaling pathway is a PTEN mutation. In some embodiments, the PTEN mutation is at residue selected from D92, G129, R130, C136, and R173. In some embodiments, the PTEN mutation is at residue selected from D92, L108, Y115, G129, R130, C136, Q149, andR173. In some embodiments, the PTEN mutation is selected from D92E, D92Y, D92H, D92V, G129E, G129V, G129R, R130Q, R130G, R130L, R130P, C136R, R173C, and R173H. In some embodiments, the PTEN mutation is selected from D92E, D92Y, D92H, D92V, L108R, Y115C, G129E, G129V, G129R, R130Q, R130G, R130L, R130P, C136R, R173C, and R173H. In some embodiments, the SERD is selected from imlunestrant, Camizestrant, fulvestrant and elacestrant.INCORPORATION BY REFERENCE

[0075] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.BRIEF DESCRIPTION OF THE DRAWINGS

[0076] The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which:

[0077] FIGs. 1A-1D illustrates pharmacodynamic and efficacy data for Compound A. FIG. 1A illustrates example in vivo measurements of AKT isoform inhibition demonstrating isoform selectivity for AKT1 inhibition over AKT2 inhibition by Compound A in the tumor tissue of the BT-474 CDX model. FIG. IB illustrates an example in vivo efficacy study in the BT-474 CDXWSGR Docket No. 61402-725.601model demonstrating single agent anti-tumor activity and tumor growth inhibition dose-response of Compound A (QD x 21 days) compared to capivasertib (150mg / kg BID 4-days on 3-days off). FIG. 1C illustrates example measurements of pAKTl inhibition in the tumor tissue at 24, 48, or 72 hours indicating Compound A had a durable pharmacodynamic effect that contributes to its antitumor activity. FIG. ID illustrates an example comparison of in vivo efficacy as measured by tumor growth inhibition for a range of dose-sizes and dosing schedules of Compound A demonstrating AUC 0-24hr and / or Cav as key exposure parameter driving antitumor activity in vivo.

[0078] FIGs. 2A-2D illustrates efficacy data for Compound A as a monotherapy in CDX models. FIG. 2A illustrates an example in vivo efficacy study evaluating the dose-response of tumor growth inhibition by Compound A, inavolisib, and capivasertib. FIG. 2B illustrates example data demonstrating the pharmacokinetic and pharmacodynamic relationship of Compound A, inavolisib, and capivasertib, highlighting isoform selectivity of Compound A over other anticancer therapies in the PI3K / AKT pathway. FIG. 2C illustrates example measurements of non-fasting glucose after administration of Compound A, inavolisib and capivasertib at pharmacologically-active doses, highlighting the role of isoform inhibition selectivity in maintaining glucose metabolism homeostasis in vivo. FIG. 2D illustrates example data demonstrating antitumor activity of Compound A and capivasertib in a PIK3CA activating hotspot mutation CDX model, KPL-4, in which a significant number of animals achieved a complete response in the Compound A arm of the study.

[0079] FIGs. 3A-3B illustrates efficacy data for Compound A as a monotherapy in MCF-7 CDX and CTG-2810 PDX models. FIG. 3A illustrates example data demonstrating antitumor activity of Compound A, inavolisib, and capivasertib in the MCF-7 CDX model, a helical domain hotspot mutation model of PIK3CA. FIG. 3B illustrates an example in vivo efficacy study of Compound A, inavolisb, STX-478, and capivasertib measuring tumor growth inhibition in the PIK3CA activated CTG-2810 PDX model.

[0080] FIGs. 4A-4D illustrates example data of the tumor growth inhibition activity of Compound A, capivasertib, inavolisib, and STX-478 as single agents or in combination in a Head and Neck Squamous Cell Carcinoma CDX model or a breast cancer model. FIG. 4A illustrates an example in vivo efficacy study measuring the tumor growth inhibition activity of Compound A, capivasertib, inavolisib, and STX-478 as single agents in the Head and Neck Squamous Cell Carcinoma CDX model, CAL-33. FIG. 4B illustrates an example in vivo efficacy study measuring the tumor growth inhibition activity of Compound A, capivasertib, inavolisib, and STX-478 as single agents in the breast cancer model, HCC-1954. FIG. 4C illustrates an example in vivo efficacy study measuring the tumor growth inhibition activity ofWSGR Docket No. 61402-725.601the combination treatment of Compound A and STX-478 in the Head and Neck Squamous Cell Carcinoma CDX model, CAL-33. FIG. 4D illustrates an example in vivo efficacy study measuring the tumor growth inhibition activity of the combination treatment of Compound A and STX-478 in the breast cancer model, HCC-1954.

[0081] FIGs. 5A-5B illustrates example in vivo efficacy studies measuring the tumor growth inhibition of fulvestrant (SERD) and Compound A as single agents and in combination together.FIG. 5A illustrates an example in vivo efficacy study measuring the tumor growth inhibition of fulvestrant (SERD) and Compound A as single agents and in combination together in the PIK3CA activated MCF-7 CDX model (CR is Complete Response). FIG. 5B illustrates an example in vivo efficacy study measuring the tumor growth inhibition of fulvestrant (SERD) and Compound A as single agents and in combination together in the PIK3CA activated BT-474 CDX model.

[0082] FIGs. 6A-6C illustrates example in vivo efficacy studies measuring the tumor growth inhibition of Compound A and capivasertib as single agents in the PTEN-null models ZR-75-1 (CDX), 786-0 (CDX), and HBCx-3 (PDX), demonstrating that significant tumor growth inhibition and tumor regressions can be accomplished with the AKT1 -selective inhibitor Compound A. FIG. 6A illustrates an example in vivo efficacy study measuring the tumor growth inhibition of Compound A and capivasertib as single agents in the PTEN-null model ZR-75-1 (CDX). FIG. 6B illustrates an example in vivo efficacy study measuring the tumor growth inhibition of Compound A and capivasertib as single agents in the PTEN-null model HBCx-3 (PDX). FIG. 6C illustrates an example in vivo efficacy study measuring the tumor growth inhibition of Compound A and capivasertib as single agents in the PTEN-null model 786-0 (CDX).

[0083] FIGs. 7A-7C illustrates example in vivo efficacy studies measuring the tumor growth inhibition of Compound A and capivasertib as single agents in AKT1 E17K activated models ST3632 (PDX), LAPC4-CR (CDX), and HBCx-2 (PDX), demonstrating that significant tumor growth inhibition and tumor regressions can be accomplished with the AKT1 -selective inhibitor Compound A in tumors harboring E17K mutations of AKT1. FIG. 7A illustrates an example in vivo efficacy study measuring the tumor growth inhibition of Compound A and capivasertib as single agents in AKT1 E17K activated model ST3632 (PDX). FIG. 7B illustrates an example in vivo efficacy study measuring the tumor growth inhibition of Compound A and capivasertib as single agents in AKT1 E17K activated model LAPC4-CR (CDX). FIG. 7C illustrates an example in vivo efficacy study measuring the tumor growth inhibition of Compound A and capivasertib as single agents in AKT1 E17K activated model HBCx-2 (PDX).WSGR Docket No. 61402-725.601

[0084] FIGs. 8A-8C illustrates efficacy data for Compound A as a monotherapy in AN3CA, SK-UT-1, and IGROV-1 CDX models in which superior efficacy was achieved in the Compound A arm compared to benchmark compounds. FIG. 8A illustrates example data demonstrating antitumor activity of Compound A, inavolisib, capivasertib, STX-478, and RLY-2608 in the AN3CA, a PTEN loss human endometrial cancer model. FIG. 8B illustrates an example in vivo efficacy study of Compound A and capivasertib measuring tumor growth inhibition in the PIK3CA activated and PTEN loss human uterine leiomyosarcoma model. FIG.8C illustrates an example in vivo efficacy study of Compound A and capivasertib measuring tumor growth inhibition in the PIK3CA activated and PTEN loss human ovarian cancer model.

[0085] FIGs. 9A-9B illustrates example in vivo efficacy study measuring the antitumor activity of palbociclib (CDK4 / 6 inhibitor) and Compound A as single agents and in combination together and comparing these effects with the benchmark compounds capivasertib and inavolisib, tested both as single agents and in combination with palbociclib. FIG. 9A illustrates an example in vivo efficacy study measuring the tumor growth inhibition of palbociclib and Compound A as single agents and in combination together, alongside capivasertib and inavolisb under the same condition in the PIK3CA activated MCF-7 CDX model. FIG. 9B illustrates an example in vivo efficacy study measuring the progression free survival (PFS) shown by Kaplan-Meier curves.

[0086] FIGs. 10A-10D illustrates pharmacodynamic and efficacy data for Compound B. FIG.10A illustrates example in vivo measurements of AKT isoform inhibition demonstrating isoform selectivity for AKT1 inhibition over AKT2 inhibition by Compound B in the tumor tissue of the BT-474, a PIK3CA activated CDX model. FIG. 10B illustrates an example in vivo efficacy study in the BT-474 CDX model demonstrating single agent anti-tumor activity and tumor growth inhibition dose-response of Compound B. FIG. 10C illustrates example measurements of pAKTl inhibition in the tumor tissue at 24, 48, or 72 hours indicating Compound B had a durable pharmacodynamic effect that contributes to its antitumor activity. FIG. 10D illustrates an example comparison of in vivo efficacy as measured by tumor growth inhibition for a range of dose-sizes and dosing schedules of Compound B demonstrating AUC 0-24hr and / or Cav as key exposure parameter driving antitumor activity in vivo.

[0087] FIGs. 11A-11D illustrates efficacy data for Compound B as a monotherapy in CDX models. FIG. 11A illustrates an example in vivo efficacy study evaluating the dose-response of tumor growth inhibition by Compound B, compared to capivasertib at 150 mg / kg BID 4 days on 3 days off in the BT-474 xenograft model. FIG. 11B illustrates example measurements of nonfasting glucose after administration of Compound B compared to capivasertib at pharmacologically-active doses, highlighting the role of isoform inhibition selectivity inWSGR Docket No. 61402-725.601maintaining glucose metabolism homeostasis in vivo. FIG. 11C illustrates example data demonstrating antitumor activity of Compound B and capivasertib in the MCF-7 CDX model, a helical domain hotspot mutation model of PIK3CA, in which superior efficacy achieved in the Compound B arm compared to capivasertib of the study. FIG. 11D illustrates example data demonstrating antitumor activity of Compound B in the T47D CDX model, a kinase domain hotspot mutation model of PIK3CA, in which a significant number of animals achieved a complete response of the study.

[0088] FIGs. 12A-12B illustrates pharmacodynamic data for Compound B in the tumor tissue of the AKT1 E17K activated LAPC4-CR CDX model. FIG. 12A illustrates example data demonstrating the pharmacokinetic and pharmacodynamic relationship of Compound B, highlighting substantial pharmacodynamic effects in a dose-dependent manner. FIG. 12B illustrates example data demonstrating the pharmacokinetic and pharmacodynamic relationship of Compound B, highlighting substantial pharmacodynamic effects in a time-dependent manner.

[0089] FIGs. 13A-13B illustrates efficacy data for Compound C in the BT-474, a PIK3CA activated CDX model. FIG. 13A illustrates an example in vivo efficacy study demonstrating significant single agent anti-tumor activity and tumor growth inhibition dose-response of Compound C. FIG. 13B illustrates example measurements of non-fasting glucose after administration of Compound C, demonstrating a dose-dependent isoform inhibition in maintaining glucose metabolism homeostasis in vivo.

[0090] FIGs. 14A-14B illustrates pharmacodynamic and efficacy data for Compound C in the AKT1 E17K activated LAPC4-CR CDX model. FIG. 14A illustrates example data demonstrating the pharmacokinetic and pharmacodynamic relationship of Compound C, highlighting substantial pharmacodynamic effects in a dose- and time-dependent manner; FIG.14B illustrates example data demonstrating significant single agent anti-tumor activity and tumor growth inhibition dose-response of Compound C.

[0091] FIGs. 15A-15B illustrates efficacy data for Compound D in the BT-474, a PIK3CA activated CDX model. FIG. 15A illustrates an example in vivo efficacy study demonstrating significant single agent anti-tumor activity and tumor growth inhibition dose-response of Compound D. FIG. 15B illustrates example measurements of non-fasting glucose after administration of Compound D, demonstrating a dose-dependent isoform inhibition in maintaining glucose metabolism homeostasis in vivo.WSGR Docket No. 61402-725.601DETAILED DESCRIPTION OF THE INVENTION

[0092] Definitions

[0093] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference.

[0094] As used in the specification and claims, the singular form “a”, “an” and “the” includes plural references unless the context clearly dictates otherwise.

[0095] In this application, the use of “or” means “and / or” unless stated otherwise. The terms “and / or” and “any combination thereof’ and their grammatical equivalents as used herein, can be used interchangeably. These terms can convey that any combination is specifically contemplated. Solely for illustrative purposes, the following phrases “A, B, and / or C” or “A, B, C, or any combination thereof’ can mean “A individually; B individually; C individually; A and B; B and C; A and C; and A, B, and C.” The term “or” can be used conjunctively or disjunctively, unless the context specifically refers to a disjunctive use.

[0096] As used in this specification and claim(s), the words “comprising” (and any form of comprising, such as “comprise” and “comprises”), “having” (and any form of having, such as “have” and “has”), “including” (and any form of including, such as “includes” and “include”) or “containing” (and any form of containing, such as “contains” and “contain”) are inclusive or open-ended and do not exclude additional, unrecited elements or method steps. It is contemplated that any embodiment discussed in this specification can be implemented with respect to any method or composition of the present disclosure, and vice versa. Furthermore, compositions and / or compounds of the present disclosure can be used to achieve methods of the present disclosure.

[0097] Reference in the specification to “some embodiments,” “an embodiment,” “one embodiment,” or “other embodiments” means that a particular feature, structure, or characteristic described in connection with the embodiments is included in at least some embodiments, but not necessarily all embodiments, of the present disclosures. To facilitate an understanding of the present disclosure, a number of terms and phrases are defined below. As used herein, the terms "treatment," "treat," and "treating" are meant to include the full spectrum of intervention for the cancer from which the subject is suffering, such as administration of the combination to alleviate, slow, stop, or reverse one or more symptoms of the cancer and to delay the progression of the cancer even if the cancer is not actually eliminated. Treatment can include, for example, a decrease in the severity of a symptom, the number of symptoms, or frequency of relapse, e.g., the inhibition of tumor growth, the arrest of tumor growth, or the regression of already existing tumors.WSGR Docket No. 61402-725.601

[0098] The term “salt” or “pharmaceutically acceptable salt” refers to salts derived from a variety of organic and inorganic counter ions well known in the art. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.

[0099] A “pharmaceutically acceptable salt” suitable for the disclosure may be an acid or base salt that is generally considered in the art to be suitable for use in contact with the tissues of human beings or animals without excessive toxicity, irritation, allergic response, or other problem or complication. Such salts include mineral and organic acid salts of basic residues such as amines, as well as alkali or organic salts of acidic residues such as carboxylic acids. Similarly, pharmaceutically acceptable cations include, but are not limited to sodium, potassium, calcium, aluminum, lithium and ammonium. Those of ordinary skill in the art will recognize from this disclosure and the knowledge in the art that further pharmaceutically acceptable salts include those listed by Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA, p. 1418 (1985). In general, a pharmaceutically acceptable acid or base salt can be synthesized from a parent compound that contains a basic or acidic moiety by any conventional chemical method. Briefly, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in an appropriate solvent.

[0100] The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0101] The terms "subject," "individual," and "patient" may be used interchangeably and refer to mammals as well as non-human mammals (e.g., non-human primates, canines, equines, felines, porcines, bovines, ungulates, lagomorphs, and the like), and "mammal" includes, but is not limited to a human. In various embodiments, the subject can be a human (e.g., adult male, adult female, adolescent male, adolescent female, male child, female child) under the care of a physician or other health worker in a hospital, as an outpatient, or other clinical context. In certain embodiments, the subject may not be under the care or prescription of a physician or other health worker.

[0102] As used herein, the phrase "a subject in need thereof refers to a subject, as described infra, that suffers from, or is at risk for, a pathology to be prophylactically or therapeutically treated with a compound or salt described herein. For example, a subject that is suffering from cancer.WSGR Docket No. 61402-725.601

[0103] The terms “administer”, “administered”, “administers” and “administering” are defined as providing a composition to a subject via a route known in the art, including but not limited to intravenous, intraarterial, oral, parenteral, buccal, topical, transdermal, rectal, intramuscular, subcutaneous, intraosseous, transmucosal, or intraperitoneal routes of administration. The terms “administer”, “administered”, “administers” and “administering” a compound should be understood to mean providing a compound of the invention or a prodrug of a compound of the invention to the individual in need.

[0104] As used herein, “treatment” or “treating” refers to an approach for obtaining beneficial or desired results with respect to a disease, disorder, or medical condition including, but not limited to, a therapeutic benefit and / or a prophylactic benefit. In certain embodiments, treatment or treating involves administering a compound or composition disclosed herein to a subject. In certain embodiments, “treatment” or “treating” refers to the administration of a compound and a second agent, or a composition thereof, as disclosed herein to a subject. In some embodiments, the second agent is selected from a platinum-based chemotherapy, a poly-ADP-ribose polymerase (PARP) inhibitor, a CDK2 inhibitor, a CDK4 / 6 inhibitor, an aromatase inhibitor, an anti-androgen, an androgen synthesis inhibitor, an mTOR inhibitor, a PI3Ka inhibitor, a PI3Ka mutant inhibitor, a gonadotropin-releasing hormone (GnRH) agonist, a selective estrogen receptor modulator (SERM), and a selective estrogen receptor degrader (SERD). A therapeutic benefit may include the eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit may be achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder, such as observing an improvement in the subject, notwithstanding that the subject may still be afflicted with the underlying disorder. Treating can include, for example, reducing, delaying or alleviating the severity of one or more symptoms of the disease or condition, or it can include reducing the frequency with which symptoms of a disease, defect, disorder, or adverse condition, and the like, are experienced by a patient. Treating can be used herein to refer to a method that results in some level of treatment or amelioration of the disease or condition, and can contemplate a range of results directed to that end, including but not restricted to prevention of the condition entirely. Treating can be used herein to refer to treating cancer. Treating cancer can be used herein to refer to a method that results in tumor volume reduction, inhibition of tumor volume growth, an increase in progression free survival, an increase in overall survival, inhibition of cell proliferation, inhibition of cancer cell proliferation, inhibition of cancer cell death, or a combination thereof. Treating cancer can be used herein to refer to a method that results in tumor volume reduction. Treating cancer can be used herein to refer to a method that results in inhibition of tumor volume growth. Treating cancer can be used herein to refer to a method thatWSGR Docket No. 61402-725.601results in an increase in progression free survival. Treating cancer can be used herein to refer to a method that results in inhibition of cell proliferation. Treating cancer can be used herein to refer to a method that results in inhibition of cancer cell proliferation. Treating cancer can be used herein to refer to a method that results in inhibition of cancer cell death.

[0105] Unless otherwise stated, structures depicted herein are meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structure except for the replacement of a hydrogen atom by a deuterium or tritium, or the replacement of a carbon atom by a 13C- or 14C -enriched carbon are within the scope of the disclosure.

[0106] Certain compounds described herein may exist in tautomeric forms, and all such tautomeric forms of the compounds being within the scope of the disclosure. Unless otherwise stated, structures depicted herein are also meant to include all stereochemical forms of the structure; i.e., the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the disclosure.

[0107] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0108] Any aspect or embodiment described herein can be combined with any other aspect or embodiment as disclosed herein.

[0109] While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.

[0110] Compounds - AKT1 Selective Inhibitors

[0111] In some aspects, the present disclosure provides methods of treatment using compounds as disclosed herein. In some embodiments, the compounds disclosed herein are used for treating cancer. In some embodiments, the compounds disclosed herein are used for treating cancer having at least one mutation in the PI3K / AKT / PTEN signaling pathway. In some embodiments, the compounds disclosed herein are used for treating a PTEN loss of function cancer. In some embodiments, the compounds disclosed herein are used for treating a PTEN deficient cancer. In some embodiments, the compounds disclosed herein are used for treating a PTEN alteredWSGR Docket No. 61402-725.601cancer. In some embodiments, the compounds disclosed herein are used for treating a PTEN mutated cancer.

[0112] In some aspects, the present disclosure provides methods of treatment using AKT1 selective inhibitor as disclosed herein. In some embodiments, the AKT1 selective inhibitors disclosed herein are used for treating cancer. In some embodiments, the AKT1 selective inhibitors disclosed herein are used for treating cancer having at least one mutation in the PI3K / AKT / PTEN signaling pathway. In some embodiments, the AKT1 selective inhibitors disclosed herein are used for treating a PTEN loss of function cancer. In some embodiments, the AKT1 selective inhibitors disclosed herein are used for treating a PTEN deficient cancer. In some embodiments, the AKT1 selective inhibitors disclosed herein are used for treating a PTEN altered cancer. In some embodiments, the AKT1 selective inhibitors disclosed herein are used for treating a PTEN mutated cancer.

[0113] In some embodiments, the compound is a compound or salt as disclosed in PCT / US2024 / 051051. In some embodiments, the compound is an AKT1 selective inhibitor. In some embodiments, the AKT1 selective inhibitor is a compound or salt as disclosed in in PCT / US2024 / 051051. In some embodiments, the AKT1 selective inhibitor is synthesized as described in PCT / US2024 / 051051. In some embodiments, Compound A or a pharmaceutically acceptable salt thereof is synthesized as described in PCT / US2024 / 051051. In some embodiments, Compound B or a pharmaceutically acceptable salt thereof is synthesized as described in PCT / US2024 / 051051. In some embodiments, Compound C or a pharmaceutically acceptable salt thereof is synthesized as described in PCT / US2024 / 051051. In some embodiments, Compound D or a pharmaceutically acceptable salt thereof is synthesized analogously as described in PCT / US2025 / 023954.

[0114] In some embodiments, the AKT1 inhibitor is also an AKT1 selective inhibitor.

[0115] In some embodiments, the AKT1 selective inhibitor is a compound represented by Formula (I):or a pharmaceutically acceptable salt thereof, wherein:R1is selected from:WSGR Docket No. 61402-725.601hydrogen, halogen, -OR10, -SR10, -N(R10)2, -NO2, and -CN;C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, -OR10, -SR10, -N(R10)2, -NO2, and -CN; andC3-8 carbocycle and 4- to 8-membered heterocycle, any of which is optionally substituted with one or more substituents independently selected from halogen, -OR10, -SR10, -N(R10)2, -NO2, -CN, C1-6 alkyl, and C1-6 haloalkyl;A1and A2are each independently selected from (i), (ii), and (iii):(i) hydrogen, halogen, -OR11, -SR11, -N(Rn)2, -C(0)N(Rn)2, -N(R11)C(O)R11, - C(O)ORn, -OC(O)Rn, -N(R11)C(O)OR11, -0C(0)N(Rn)2, -N(R11)C(O)N(R11)2, -S(O)Rn, -S(O)2Rn, -N(R11)S(O)2R11, -S(O)2N(RU)2, -NO2, and -CN;(ii) C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any of which is optionally substituted with one or more substituents independently selected from:halogen=N(Rn), and -CN; and4- to 10-membered heterocycle and C3-10 carbocycle, any of which is optionally substituted with one or more substituents independently selected from: halogen, -OR11, -SR11, -N(Rn)2, -C(O)R11, -C(O)N(R11)2, -N(R11)C(O)R11, -N(R11)S(O)2R11, -C(O)OR11, -OC(O)R11, -S(O)2Rn, -S(O)2N(RU)2, -NO2, =0, =S, =N(Rn), and -CN; and(iii) 4- to 10-membered heterocycle and C3-10 carbocycle, any of which is optionally substituted with one or more substituents independently selected from: halogen, -OR11, -SR11, -N(Rn)2, -C(0)Rn, -C(0)N(Rn)2, -N(R11)C(0)R11, --NO2, =0, =S, =N(Rn), and -CN;C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any one of which is optionally substituted with one or more substituents independently selected from: halogen, -OR11, -SR11, -N(Rn)2, -C(0)Rn, -C(0)N(Rn)2, - N R^ O11, -C(0)0Rn, -0C(0)Rn, -N^C^OR11, - 0C(0)N(Rn)2, -N(R11)C(0)N(R11)2, -S(O)Rn, -S(0)2RU, - N(R11)S(0)2R11, -S(O)2N(RU)2, -NO2, =0, =S, =N(Rn), and -CN; andWSGR Docket No. 61402-725.601C3-10 carbocycle and 3- to 10-membered heterocycle, any of which is optionally substituted with one or more substituents independently selected from: halogen, -OR11, -N(Rn)2, -C(O)Rn, -C(O)N(R11)2, -N(R11)C(O)R11, -C(O)OR11, -OC(O)R11, -NO2, =0, =S, =N(Rn), -CN;C1-6 alkyl C2-6 alkenyl, and C3-6 alkynyl, any one of which is optionally substituted with one or more substituents independently selected from: halogen, -OR11, -SR11, -N(Rn)2, -C(O)R11, -C(O)N(R11)2, -N(R11)C(O)R11, -N(R11)S(O)2R11, -C(O)OR11, -OC(O)R11, -NO2, =0, =S, =N(Rn), and -CN; andC3-10 carbocycle and 4- to 10-membered heterocycle any one of which is optionally substituted with one or more substituents independently selected from: halogen, -OR11, -SR11, -N(R11)2, -C(O)R11, -N(R11)C(O)N(R11)2, -N(R11)S(O)2R11, -C(O)OR11, -OC(O)R11,-6 alkyl;R3is independently selected at each instance from:halogen, -OR13, -SR13, -N(R13)2, -C(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -C(O)OR13, -OC(O)R13, -NO2, and -CN; andC1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any one of which is optionally substituted with one or more substituents independently selected from: halogen, -OR13, -SR13, - N(R13)2, -C(O)R13, -C(O)N(R13)2, -N(R13)C(O)R13, -C(O)OR13, -OC(O)R13, - NO2, =0, =S, =N(R13), and -CN;R4is independently selected at each instance from:halogen, -OR14, -SR14, -N(R14)2, -C(O)R14, -C(O)N(R14)2, -N(R14)C(O)R14, -C(O)OR14, -OC(O)R14, -NO2, =0, =S, =N(R14), and -CN; andC1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any one of which is optionally substituted with one or more substituents independently selected from halogen, -OR14, -SR14, - N(R14)2, -C(O)R14, -C(O)N(R14)2, -N(R14)C(O)R14, -C(O)OR14, -OC(O)R14, - NO2, =0, =S, =N(R14), and -CN;L is represented by -L1-L2-L3-L4-, wherein L1, L2, L3, and L4are each independently selected from (a) and (b):(a) -0-, -N(R15)-, -S-, -S(0)-, -S(0)2-, -S(O)(NR15)-, -N(R15)C(0)-, -N(R15)C(0)0-, -N(R15)S(O)2-, -N(R15)S(O)2N(R15)-, -S(O)(NR15)N(R15)-, -N(R15)N(R15)-, - (R15)NC(O)N(R15)-, and -(R15)NC(O)N(R15)N(R15)-; and(b) C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, C3-8 carbocyclene, and 3- to 8- membered heterocyclene, any of which is optionally substituted with one or moreWSGR Docket No. 61402-725.601substituents independently selected from halogen, -OR15, -SR15, =0, =S, and - CN;wherein L1, L2, L3, and L4are each optionally absent;wherein no more than two of L1, L2, L3, and L4are selected from (a) and the two selected are not adjacent;Ring B selected from 3- to 10-membered heterocyclene and C3-10 carbocyclene, any of which is optionally substituted with one or more substituents independently selected from: halogen, -OR16, -SR16, -N(R16)2, -C(O)N(R16)2, -C(O)OR16, -OC(O)R16, -N(R16)C(O)R16, -N(R16)S(O)2R16, -S(O)2N(R16)2, -N(R16)C(O)N(R16)2, -N(R16)C(O)OR16, - OC(O)N(R16)2, -S(O)R16, -S(O)2R16, -NO2, =0, =S, =N(R16), and -CN;C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR16, -SR16, - N(R16)2, -C(O)N(R16)2, -C(O)OR16, -OC(O)R16, -N(R16)C(O)R16, - N(R16)S(O)2R16, -S(O)2N(R16)2, -N(R16)C(O)N(R16)2, -N(R16)C(O)OR16, - OC(O)N(R16)2, -S(O)R16, -S(O)2R16, -NO2, =0, =S, =N(R16), and -CN; and 3- to 6-membered heterocycle and C3-6 carbocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, C1-6 alkyl, C1-6 haloalkyl, -OR16, -SR16, -N(R16)2, -C(O)N(R16)2, -C(O)OR16, - OC(O)R16, -N(R16)C(O)R16, -N(R16)S(O)2R16, -S(O)2N(R16)2, - N(R16)C(O)N(R16)2, -N(R16)C(O)OR16, -OC(O)N(R16)2, -S(O)R16, -S(O)2R16, - NO2, =0, =S, =N(R16), and -CN;Ring D is selected from:A mn,,,;R2is independently selected at each instance from halogen, Ci-6 alkyl, Ci-6 haloalkyl, -OR12, - SR12, -N(R12)2, -NO2, and -CN;A3is cysteine susceptible electrophile;R10, R11, R12, R13, R14, R15, and R16are each independently selected at each occurrence from:hydrogen,C1-6 alkyl, optionally substituted with one or more substituents independently selected from halogen, -OH, -O-C1-6 alkyl, -O-C1-6 haloalkyl, C3-6 carbocycle, and 3- to 6- membered heterocycle; andC3-6 carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -O- C1-6 alkyl, -O-C1-6 haloalkyl, C1-6 alkyl, and C1-6 haloalkyl;WSGR Docket No. 61402-725.601m is selected from 0, 1, 2, and 3;n is selected from 0, 1, 2, and 3;q is selected from 1, 2, and 3; andp is selected from 0, 1, 2, 3, 4, and 5.

[0116] In some embodiments, for the compound or salt of Formula (I), the cysteine susceptible electrophile is selected from a haloacetamide, a haloalkyl ketone, a halo amidine, a halo benzylphosphonate, an acyloxyalkyl ketone, a sulfonyl oxirane, an epoxide, a diazoalkyl ketone, a halotriazine, an acrylamide, a cyano acrylamide, a vinyl sulfone, a vinyl sulfonamide, an acrylate, a fumarate, a carbonyl acrylate, a maleimide, a ketoamide, a nitrile, an alkene, an alkyne, a keto heterocycle, and an ynamide. In some embodiments, the cysteine susceptible electrophile is selected from a haloacetamide, a haloalkyl ketone, and a halo amidine. In some embodiments, the cysteine susceptible electrophile is selected from an acrylate group, an acrylamide group, a vinyl group, a vinylsulfone group, a vinylsulfonamide group, an ynamide, an alkene, an alkyne, and an epoxide group. In some embodiments, the cysteine susceptible electrophile is selected from an acrylate group, an acrylamide group, a vinylsulfone group, a vinylsulfonamide group, an alkene, and an alkyne. In some embodiments, the cysteine susceptible electrophile is selected from an acrylate group, an acrylamide group, an alkene, and an alkyne.

[0117] In some embodiments, A3is selected from:-C(O)R17, -S(O)2R17, -N(R19)C(O)(R17), -C(O)N(R17)(R19), -N(R19)S(O)2R17, -S(O)2N(R17)(R19), and -CN;Ci-6 alkyl substituted with one or more substituents independently selected from -C(O)R17, - S(O)2R17, -N(R19)C(O)(R17), -C(O)N(R17)(R19), and -N(R19)S(O)2R17, -S(O)2N(R17)(R19), and -CN;C2-6 alkenyl and C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from -C(O)R19, -S(O)2R19, -N(R19)C(O)(R19), - C(O)N(R19)2, -N(R19)S(O)2R19, -S(O)2N(R19)(R19), and -CN; andC3-6 carbocycle and 3- to 6- membered heterocycle, each of which is substituted with one or more substituents independently selected from =0, C2-6 alkenyl, C2-6 alkynyl, -C(O)R17, - S(O)2R17, -N(R19)C(O)(R17), -C(O)N(R17)(R19), -N(R19)S(O)2R17, -S(O)2N(R17)(R19), and -CN;R17is independently selected at each occurrence from:C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl each of which is optionally substituted with one or more substituents independently selected from halogen, -OR18, -SR18, -N(R18)2, -C(O)N(R18)2, -C(O)OR18, -OC(O)R18, -N(R18)C(O)R18, -WSGR Docket No. 61402-725.601N(R18)S(O)2R18, -S(O)2N(R18)2, -N(R18)C(O)N(R18)2, -N(R18)C(O)OR18, - OC(O)N(R18)2, -S(O)R18, -S(O)2R18, -NO2, and -CN; andC3-6 carbocyclenyl, 3- to 6- membered heterocyclenyl, and 3- to 6- membered heterocyclyl, each of which is optionally substituted with one or more substituents independently selected from halogen, C1-6 alkyl, C1-6 haloalkyl, halogen, -OR18, -SR18, -N(R18)2, -C(O)N(R18)2, -C(O)OR18, -OC(O)R18, - N(R18)C(O)R18, -N(R18)S(O)2R18, -S(O)2N(R18)2, -N(R18)C(O)N(R18)2, - N(R18)C(O)OR18, -OC(O)N(R18)2, -S(O)R18, -S(O)2R18, -NO2, and -CN; and R18and R19are each independently selected at each occurrence from: hydrogen, C1-6 alkyl, C1-6 haloalkyl, C3-6 carbocycle, and 3- to 6-membered heterocycle.

[0118] In some embodiments, the compound is l-(4-((5-(2-(2-aminopyridin-3-yl)-5-(lH-pyrazol- 1 -yl)-3H-imidazo[4,5-b]pyri din-3 -yl)-2, 3 -dihydro- IH-inden- 1 -yl)amino)piperidin- 1 -yl)prop-2-en-l-one or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is l-(4-((5-(2-(2-aminopyridin-3-yl)-5-(lH-pyrazol-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-lH-inden-l-yl)amino)piperidin-l-yl)prop-2-en-l-one. In some embodiments,the compoundpharmaceutically acceptable salt thereof. In someembodiments, the compound is

[0119] In some embodiments, the compound is (S)-l-(4-((5-(2-(2-aminopyridin-3-yl)-5-(lH-pyrazol- 1 -yl)-3H-imidazo[4,5-b]pyri din-3 -yl)-2, 3 -dihydro- IH-inden- 1 -yl)amino)piperidin- 1 -yl)prop-2-en-l-one or a pharmaceutically salt thereof. In some embodiment, the compound is (S)-l-(4-((5-(2-(2-aminopyridin-3-yl)-5-(lH-pyrazol-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro- IH-inden- l-yl)amino)piperidin-l-yl)prop-2-en-l -one. In some embodiments, theWSGR Docket No. 61402-725.601pharmaceutically acceptable salt thereof. In someembodiments, the compound is

[0120] In some embodiments, the compound is Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, Compound A is (S)-l-(4-((5-(2-(2-aminopyridin-3-yl)-5- (lH-pyrazol-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-lH-inden-l-yl)amino)piperidin-l-yl)prop-2-en-l-one. In some embodiments, Compoundembodiments, the compound is Compound A.

[0121] In some embodiments, the AKT1 selective inhibitor is l-(4-((5-(2-(2-aminopyridin-3-yl)- 5-(lH-pyrazol-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-lH-inden-l- yl)amino)piperidin-l-yl)prop-2-en-l-one or a pharmaceutically acceptable salt thereof. In some embodiments, the AKT1 selective inhibitor is l-(4-((5-(2-(2-aminopyridin-3-yl)-5-(lH-pyrazol- l-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-lH-inden-l-yl)amino)piperidin-l-yl)prop-2-en-l-one. In some embodiments, the AKT1 selective inhibitor isWSGR Docket No. 61402-725.601pharmaceutically acceptable salt thereof. In some embodiments, the AKT1 selective inhibitor is

[0122] In some embodiments, the AKT1 selective inhibitor is (S)-l-(4-((5-(2-(2-aminopyridin- 3-yl)-5-(lH-pyrazol-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-lH-inden-l-yl)amino)piperidin-l-yl)prop-2-en-l-one or a pharmaceutically salt thereof. In some embodiment, the AKT1 selective inhibitor is (S)-l-(4-((5-(2-(2-aminopyridin-3-yl)-5-(lH-pyrazol- 1 -yl)-3H-imidazo[4,5-b]pyri din-3 -yl)-2, 3 -dihydro- IH-inden- 1 -yl)amino)piperidin- 1 -yl)prop-2-en-l-one. In some embodiments, the AKT1 selective inhibitor is, or a pharmaceutically acceptable salt thereof. In some embodiments the AKT1 selective

[0123] In some embodiments, the AKT1 selective inhibitor is Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, Compound A is (S)-l-(4-((5-(2- (2-aminopyridin-3-yl)-5-(lH-pyrazol-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-lH-inden-l-yl)amino)piperidin-l-yl)prop-2-en-l-one. In some embodiments, Compound A issome embodiments, the AKT1 selective inhibitor is Compound A.WSGR Docket No. 61402-725.601

[0124] In some embodiments, the compound is l-(4-((5-(2-(2-aminopyridin-3-yl)-5-(lH-pyrazol-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2-fluoro-2,3-dihydro-lH-inden-l-yl)amino)piperidin-l-yl)prop-2-en-l-one or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is l-(4-((5-(2-(2-aminopyridin-3-yl)-5-(lH-pyrazol-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2-fluoro-2,3-dihydro-lH-inden-l-yl)amino)piperidin-l-yl)prop-2-en-l-one. In some embodiments, the compound isacceptable salt thereof. In some embodiments, the compound

[0125] In some embodiments, the compound is l-(4-(((lR,2S)-5-(2-(2-aminopyridin-3-yl)-5-( IH-pyrazol- 1 -yl)-3H-imidazo[4, 5-b]pyri din-3 -yl)-2-fluoro-2, 3 -dihydro- IH-inden- 1 -yl)amino)piperidin-l-yl)prop-2-en-l-one or a pharmaceutically salt thereof. In some embodiment, the compound is l-(4-(((lR,2S)-5-(2-(2-aminopyridin-3-yl)-5-(lH-pyrazol-l-yl)- 3H-imidazo[4,5-b]pyridin-3-yl)-2-fluoro-2,3-dihydro-lH-inden-l-yl)amino)piperidin-l-yl)prop-2-en-l-one. In some embodiments, the compound isWSGR Docket No. 61402-725.601pharmaceutically acceptable salt thereof. In some embodiments, the compound is

[0126] In some embodiments, the compound is Compound B or a pharmaceutically acceptable salt thereof. In some embodiments, Compound B is l-(4-(((lR,2S)-5-(2-(2-aminopyridin-3-yl)- 5-(lH-pyrazol-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2-fluoro-2,3-dihydro-lH-inden-l-yl)amino)piperidin-l-yl)prop-2-en-l-one. In some embodiments, Compound B issome embodiments, the compound is Compound B.

[0127] In some embodiments, the AKT1 selective inhibitor is l-(4-((5-(2-(2-aminopyridin-3-yl)-5-(lH-pyrazol-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2-fluoro-2,3-dihydro-lH-inden-l-yl)amino)piperidin-l-yl)prop-2-en-l-one or a pharmaceutically acceptable salt thereof. In some embodiments, the AKT1 selective inhibitor is l-(4-((5-(2-(2-aminopyridin-3-yl)-5-(lH-pyrazol-1 -yl)-3H-imidazo[4,5-b]pyri din-3 -yl)-2-fluoro-2, 3 -dihydro- IH-inden- 1 -yl)amino)piperidin- 1 -yl)prop-2-en-l-one. In some embodiments, the AKT1 selective inhibitor isWSGR Docket No. 61402-725.601pharmaceutically acceptable salt thereof. In some embodiments, theAKT1 selective inhibitor is

[0128] In some embodiments, the AKT1 selective inhibitor is l-(4-(((lR,2S)-5-(2-(2- aminopyridin-3-yl)-5-(lH-pyrazol-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2-fluoro-2,3-dihydro- lH-inden-l-yl)amino)piperidin-l-yl)prop-2-en-l-one or a pharmaceutically salt thereof. In some embodiments, the AKT1 selective inhibitor is l-(4-(((lR,2S)-5-(2-(2-aminopyridin-3-yl)-5-(lH- pyrazol-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2-fluoro-2,3-dihydro-lH-inden-l-yl)amino)piperidin-l-yl)prop-2-en-l-one. In some embodiments, the AKT1 selective inhibitor ispharmaceutically acceptable salt thereof. In some embodiments the

[0129] In some embodiments, the AKT1 selective inhibitor is Compound B or a pharmaceutically acceptable salt thereof. In some embodiments, Compound B is l-(4-(((lR,2S)- 5-(2-(2-aminopyridin-3-yl)-5-(lH-pyrazol-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2-fluoro-2,3- dihydro- lH-inden-l-yl)amino)piperidin-l-yl)prop-2-en-l -one. In some embodiments,WSGR Docket No. 61402-725.601some embodiments, the AKT1 selective inhibitor is Compound B.

[0130] In some embodiments, the compound is l-(4-((5-(2-(2-aminopyridin-3-yl)-5-(pyridin-2- yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-lH-inden-l-yl)amino)piperidin-l-yl)prop-2-en- 1-one or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 1 - (4-((5-(2-(2-aminopyridin-3-yl)-5-(pyridin-2-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro- lH-inden-l-yl)amino)piperidin-l-yl)prop-2-en-l-one. In some embodiments, the compound is

[0131] In some embodiments, the compound is (S)-l-(4-((5-(2-(2-aminopyridin-3-yl)-5- (pyridin-2-yl)-3H-imidazo[4, 5 -b ]py ri din-3 -yl)-2, 3 -dihydro- IH-inden- 1 -yl)amino)piperidin- 1 - yl)prop-2-en-l-one or a pharmaceutically salt thereof. In some embodiment, the compound is (S)-l-(4-((5-(2-(2-aminopyridin-3-yl)-5-(pyridin-2-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3- dihydro- lH-inden-l-yl)amino)piperidin-l-yl)prop-2-en-l -one. In some embodiments, theWSGR Docket No. 61402-725.601

[0132] In some embodiments, the compound is Compound C or a pharmaceutically acceptable salt thereof. In some embodiments, Compound C is (S)-l-(4-((5-(2-(2-aminopyridin-3-yl)-5- (pyridin-2-yl)-3H-imidazo[4, 5-b]pyri din-3 -yl)-2, 3 -dihydro- IH-inden- 1 -yl)amino)piperidin- 1 -yl)prop-2-en-l-one. In some embodiments, Compoundembodiments, the compound is Compound C.

[0133] In some embodiments, the AKT1 selective inhibitor is l-(4-((5-(2-(2-aminopyridin-3-yl)- 5-(pyridin-2-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-lH-inden-l-yl)amino)piperidin-l- yl)prop-2-en-l-oneor a pharmaceutically acceptable salt thereof. In some embodiments, the AKT1 selective inhibitor is l-(4-((5-(2-(2-aminopyridin-3-yl)-5-(pyridin-2-yl)-3H-imidazo[4,5- b]pyri din-3 -yl)-2, 3 -dihydro- IH-inden- 1 -yl)amino)piperidin- 1 -yl)prop-2-en- 1 -one. In someembodiments, the AKT1 selective inhibitorWSGR Docket No. 61402-725.601acceptable salt thereof. In some embodiments, the AKT1 selective inhibitor is

[0134] In some embodiments, the AKT1 selective inhibitor is (S)-l-(4-((5-(2-(2-aminopyridin-3-yl)-5-(pyridin-2-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-lH-inden-l-yl)amino)piperidin-l-yl)prop-2-en-l-one or a pharmaceutically salt thereof. In some embodiment, the AKT1 selective inhibitor is (S)-l-(4-((5-(2-(2-aminopyridin-3-yl)-5-(pyridin-2-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-lH-inden-l-yl)amino)piperidin-l-yl)prop-2-en-1-one. In some embodiments, the AKT1 selective inhibitor ipharmaceutically acceptable salt thereof. In some embodiments the AKT1 selective inhibitor is

[0135] In some embodiments, the AKT1 selective inhibitor is Compound C or a pharmaceutically acceptable salt thereof. In some embodiments, Compound C is (S)-l-(4-((5-(2-(2-aminopyridin-3-yl)-5-(pyridin-2-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-lH-inden- l-yl)amino)piperidin-l-yl)prop-2-en-l-one. In some embodiments, Compound C issome embodiments, the AKT1 selective inhibitor is Compound C.WSGR Docket No. 61402-725.601

[0136] In some embodiments, the compound is l-(4-((5-(2-(2-aminopyridin-3-yl)-5-(3-(4-(l- m ethyl- lH-pyrazol-3 -yl)piperazin- 1 -yl)- IH-pyrazol- 1 -yl)-3H-imidazo[4, 5 -b ] py ri din-3 -yl)-2,3 - dihydro-lH-inden-l-yl)amino)piperidin-l-yl)prop-2-en-l-one or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is l-(4-((5-(2-(2-aminopyridin-3-yl)-5-(3-(4- ( 1 -methyl- lH-pyrazol-3 -yl)piperazin- 1 -yl)- IH-pyrazol- 1 -yl)-3H-imidazo[4, 5-b]pyri din-3 -yl)- 2,3-dihydro-lH-inden-l-yl)amino)piperidin-l-yl)prop-2-en-l-one. In some embodiments, thepharmaceutically acceptable saltthereof. In some embodiments, the compound

[0137] In some embodiments, the compound is (S)-l-(4-((5-(2-(2-aminopyridin-3-yl)-5-(3-(4- ( 1 -methyl- lH-pyrazol-3 -yl)piperazin- 1 -yl)- IH-pyrazol- 1 -yl)-3H-imidazo[4, 5-b]pyri din-3 -yl)- 2.3-dihydro-lH-inden-l-yl)amino)piperidin-l-yl)prop-2-en-l-one or a pharmaceutically salt thereof. In some embodiment, the compound is (S)-l-(4-((5-(2-(2-aminopyridin-3-yl)-5-(3-(4- ( 1 -methyl- lH-pyrazol-3 -yl)piperazin- 1 -yl)- IH-pyrazol- 1 -yl)-3H-imidazo[4, 5-b]pyri din-3 -yl)- 2.3-dihydro-lH-inden-l-yl)amino)piperidin-l-yl)prop-2-en-l-one. In some embodiments, thecompound ipharmaceutically acceptable saltthereof. In some embodiments the compound iWSGR Docket No. 61402-725.601

[0138] In some embodiments, the compound is Compound D or a pharmaceutically acceptable salt thereof. In some embodiments, Compound D is (S)-l-(4-((5-(2-(2-aminopyridin-3-yl)-5-(3- (4-(l-methyl-lH-pyrazol-3-yl)piperazin-l-yl)-lH-pyrazol-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl)- 2,3-dihydro-lH-inden-l-yl)amino)piperidin-l-yl)prop-2-en-l-one. In some embodiments,some embodiments, the compound is Compound D.

[0139] In some embodiments, the AKT1 selective inhibitor is l-(4-((5-(2-(2-aminopyridin-3-yl)- 5-(3-(4-(l-methyl-lH-pyrazol-3-yl)piperazin-l-yl)-lH-pyrazol-l-yl)-3H-imidazo[4,5-b]pyridin- 3-yl)-2,3-dihydro-lH-inden-l-yl)amino)piperidin-l-yl)prop-2-en-l-one or a pharmaceutically acceptable salt thereof. In some embodiments, the AKT1 selective inhibitor is l-(4-((5-(2-(2- aminopyridin-3-yl)-5-(3-(4-(l-methyl-lH-pyrazol-3-yl)piperazin-l-yl)-lH-pyrazol-l-yl)-3H- imidazo[4,5-b]pyri din-3 -yl)-2, 3 -dihydro- IH-inden- 1 -yl)amino)piperidin- 1 -yl)prop-2-en- 1 -one.In some embodiments, the AKT1 selective inhibitor ia pharmaceutically acceptable salt thereof. In some embodiments, the AKT1 selective inhibitor

[0140] In some embodiments, the AKT1 selective inhibitor is (S)-l-(4-((5-(2-(2-aminopyridin- 3-yl)-5-(3-(4-(l-methyl-lH-pyrazol-3-yl)piperazin-l-yl)-lH-pyrazol-l-yl)-3H-imidazo[4,5- b]pyri din-3 -yl)-2, 3 -dihydro- IH-inden- 1 -yl)amino)piperidin- 1 -yl)prop-2-en- 1 -one or a pharmaceutically salt thereof. In some embodiment, the AKT1 selective inhibitor is (S)-l-(4-((5- (2-(2-aminopyridin-3-yl)-5-(3-(4-(l-methyl-lH-pyrazol-3-yl)piperazin-l-yl)-lH-pyrazol-l-yl)-WSGR Docket No. 61402-725.6013H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-lH-inden-l-yl)amino)piperidin-l-yl)prop-2-en-l-one. In some embodiments, the AKT1 selective inhibitor ispharmaceutically acceptable salt thereof. In someembodiments the AKT1 selective inhibitor

[0141] In some embodiments, the AKT1 selective inhibitor is Compound D or a pharmaceutically acceptable salt thereof. In some embodiments, Compound D is ((S)-l-(4-((5- (2-(2-aminopyridin-3-yl)-5-(3-(4-(l-methyl-lH-pyrazol-3-yl)piperazin-l-yl)-lH-pyrazol-l-yl)- 3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-lH-inden-l-yl)amino)piperidin-l-yl)prop-2-en-l-one. In some embodiments, Compoundembodiments, the AKT1 selective inhibitor is Compound D.

[0142] In an aspect of the present disclosure is a compound ofpharmaceutically acceptable salt thereof.WSGR Docket No. 61402-725.601

[0143] In an aspect of the present disclosure is a pharmaceutical composition comprisingpharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0144] Mutations

[0145] The methods presented herein may be used to treat cancer. In some embodiments, the methods presented herein can be used to treat a genetically defined subset of cancer. In some embodiments, the methods presented herein can be used to treat a subject diagnosed with cancer. In some embodiments, the methods presented herein can be used to treat a subject diagnosed with subset of cancer.

[0146] In some embodiments, the method comprises treating a cancer having at least one mutation in the PI3K / AKT / PTEN signaling pathway. In some embodiments, the method comprises identifying a subject with at least one mutation in the PI3K / AKT / PTEN signaling pathway. In some embodiments, the method comprises selecting a subject with at least one mutation in the PI3K / AKT / PTEN signaling pathway. In some embodiments, the method comprises screening to identify a subject with at least one mutation in the PI3K / AKT / PTEN signaling pathway. In some embodiments, the subject has at least one mutation in the PI3K / AKT / PTEN signaling pathway. In some embodiments, the subject has at least one mutation in the PTEN.

[0147] In some embodiments, the at least one mutation in the PI3K / AKT / PTEN signaling pathway comprises a loss of function mutation. In some embodiments, the at least one mutation in the PI3K / AKT / PTEN signaling pathway results in a PTEN loss of function cancer. In some embodiments, the at least one mutation in the PI3K / AKT / PTEN signaling pathway results in a PTEN deficient cancer. In some embodiments, the at least one mutation in the PI3K / AKT / PTEN signaling pathway results in a PTEN altered cancer. In some embodiments, the at least one mutation in the PI3K / AKT / PTEN signaling pathway results in a PTEN mutated cancer. In some embodiments, the at least one mutation in the PI3K / AKT / PTEN signaling pathway results in misregulation of the PI3K / AKT / PTEN signaling pathway. In some embodiments, the at least one mutation in the PI3K / AKT / PTEN signaling pathway results in hyperactivation of the PI3K / AKT / PTEN signaling pathway. In some embodiments, the at least one mutation in theWSGR Docket No. 61402-725.601PI3K / AKT / PTEN signaling pathway results in upregulation of the PI3K / AKT / PTEN signaling pathway.

[0148] In some embodiments, the at least one mutation in the PI3K / AKT / PTEN signaling pathway is an insertion, a deletion, a substitution at a residue, or a combination thereof. In some embodiments, the at least one mutation in the PI3K / AKT / PTEN signaling pathway is an insertion, a deletion, or a substitution at a residue. In some embodiments, the at least one mutation in the PI3K / AKT / PTEN signaling pathway is an insertion at a residue. In some embodiments, the at least one mutation in the PI3K / AKT / PTEN signaling pathway is a deletion at a residue. In some embodiments, the at least one mutation in the PI3K / AKT / PTEN signaling pathway is a substitution at a residue. In some embodiments, the residue is in a protein selected from PI3K, AKT1, and PTEN. In some embodiments, the residue is in a protein selected from PIK3CA, AKT1, and PTEN. In some embodiments, the residue is at a gene encoding a protein selected from PI3K, AKT1, and PTEN. In some embodiments, the residue is at a gene encoding a protein selected from PIK3CA, AKT1, and PTEN.

[0149] In some embodiments, the at least one mutation in the PI3K / AKT / PTEN signaling pathway is an insertion, a deletion, a substitution, or a combination thereof at a gene encoding a protein of the PI3K / AKT / PTEN signaling pathway. In some embodiments, the at least one mutation in the PI3K / AKT / PTEN signaling pathway is an insertion, a deletion, a substitution, or a combination thereof at a gene encoding a protein of the PI3K / AKT / PTEN signaling pathway. In some embodiments, the at least one mutation in the PI3K / AKT / PTEN signaling pathway is an insertion at a gene encoding a protein of the PI3K / AKT / PTEN signaling pathway. In some embodiments, the at least one mutation in the PI3K / AKT / PTEN signaling pathway is a deletion at a gene encoding a protein of the PI3K / AKT / PTEN signaling pathway. In some embodiments, the at least one mutation in the PI3K / AKT / PTEN signaling pathway is a substitution at a gene encoding a protein of the PI3K / AKT / PTEN signaling pathway.

[0150] In some embodiments, the at least one mutation in the PI3K / AKT / PTEN signaling pathway is an insertion, a deletion, or a combination thereof at a gene encoding a protein of the PI3K / AKT / PTEN signaling pathway that results in a frameshift mutation. In some embodiments, the frameshift mutation results in the protein being nonfunctional.

[0151] In some embodiments, the at least one mutation in the PI3K / AKT / PTEN signaling pathway is a substitution at a gene encoding a protein of the PI3K / AKT / PTEN signaling pathway that results in a missense mutation or nonsense mutation. In some embodiments, the missense mutation or nonsense mutation results in the protein being nonfunctional. In some embodiments, the missense mutation results in the protein being hyperactivated. In some embodiments, the missense mutation results in the protein being overexpressed. In someWSGR Docket No. 61402-725.601embodiments, the protein is PIK3CA. In some embodiments, the protein is AKT1. In some embodiments, the protein is PIK3CA. In some embodiments, the protein is PTEN.

[0152] In some embodiments, the at least one mutation results in a mutated PIK3CA, AKT1, PTEN, or a combination thereof. In some embodiments, the at least one mutation results in a mutated PIK3CA, AKT1, or PTEN. In some embodiments, the at least one mutation results in a mutated PIK3CA. In some embodiments, the at least one mutation results in a mutated AKT1. In some embodiments, the at least one mutation results in a mutated PTEN.

[0153] In some embodiments, the at least one mutation in the PI3K / AKT / PTEN signaling pathway comprises a PIK3CA mutation. In some embodiments, the PIK3CA mutation is at a residue selected from R38, R88, R93, G106, K111, G118, C124, K342, N345, C420, E453, E542, E545, Q546, M1043, H1047, and G1049. In some embodiments, the PIK3CA mutation is at a residue selected from R88, R93, G106, K111, G118, N345, C420, E453, E542, E545, Q546, M1043, H1047, and G1049. In some embodiments, the PIK3CA mutation is at residue R38. In some embodiments, the PIK3CA mutation is at residue R88. In some embodiments, the PIK3CA mutation is at residue R93. In some embodiments, the PIK3CA mutation is at residue G106. In some embodiments, the PIK3CA mutation is at residue K111. In some embodiments, the PIK3CA mutation is at residue G118. In some embodiments, the PIK3CA mutation is at residue C124. In some embodiments, the PIK3CA mutation is at residue K342. In some embodiments, the PIK3CA mutation is at residue N345. In some embodiments, the PIK3CA mutation is at residue C420. In some embodiments, the PIK3CA mutation is at residue E453. In some embodiments, the PIK3CA mutation is at residue E542. In some embodiments, the PIK3CA mutation is at residue E545. In some embodiments, the PIK3CA mutation is at residue Q546. In some embodiments, the PIK3CA mutation is at residue M1043. In some embodiments, the PIK3CA mutation is at H1047. In some embodiments, the PIK3CA mutation is at residue G1049. For example, a PIK3CA mutation at R88 means a substitution from an arginine (R) to an amino acid other than arginine (R) at the amino acid position of 88 in the protein PIK3CA.

[0154] In some embodiments, the at least one mutation in the PI3K / AKT / PTEN signaling pathway is a AKT1 mutation. In some embodiments, the AKT1 mutation is at residue E17. For example, a AKT1 mutation at El 7 means a substitution from a glutamic acid (E) to an amino acid other than glutamic acid (E) at the amino acid position of 17 in the protein AKT1. In some embodiments, the AKT1 mutation is E17K. For example, a AKT1 mutation at E17K means a substitution from a glutamic acid (E) to a lysine (K) at the amino acid position of 17 in the protein AKT1.

[0155] In some embodiments, the at least one mutation in the PI3K / AKT / PTEN signaling pathway is a PTEN mutation. In some embodiments, the PTEN mutation is at residue selectedWSGR Docket No. 61402-725.601from D92, L108, Y115, G129, R130, C136, Q149, and R173. In some embodiments, the PTEN mutation is at residue selected from D92, G129, R130, C136, and R173. In some embodiments, the PTEN mutation is selected from D92E, D92Y, D92H, D92V, L108R, Y115C, G129E, G129V, G129R, R130Q, R130G, R130L, R130P, C136R, R173C, and R173H. In some embodiments, the PTEN mutation is selected from D92E, D92Y, D92H, D92V, G129E, G129V, G129R, R130Q, R130G, R130L, R130P, C136R, R173C, and R173H. In some embodiments, the PTEN mutation is at residue D92. In some embodiments, the PTEN mutation is at residue L108. In some embodiments, the PTEN mutation is at residue Y115. In some embodiments, the PTEN mutation is at residue G129. In some embodiments, the PTEN mutation is at residue R130. In some embodiments, the PTEN mutation is at residue C136. In some embodiments, the PTEN mutation is at residue Q149. In some embodiments, the PTEN mutation is at residue R173. For example, a PTEN mutation at D92 means a substitution from an aspartic acid (D) to an amino acid other than aspartic acid (D) at the amino acid position of 92 in the protein PTEN. In some embodiments, the PTEN mutation is D92E. In some embodiments, the PTEN mutation is D92Y. In some embodiments, the PTEN mutation is D92H. In some embodiments, the PTEN mutation is D92V. In some embodiments, the PTEN mutation is L108R. In some embodiments, the PTEN mutation is Y115C. In some embodiments, the PTEN mutation is G129E. In some embodiments, the PTEN mutation is G129V. In some embodiments, the PTEN mutation is G129R. In some embodiments, the PTEN mutation is R130Q. In some embodiments, the PTEN mutation is R130G. In some embodiments, the PTEN mutation is R130L. In some embodiments, the PTEN mutation is R130P. In some embodiments, the PTEN mutation is C136R. In some embodiments, the PTEN mutation is R173C. In some embodiments, the PTEN mutation is R173H. For example, a PTEN mutation at D92E means a substitution from an aspartic acid (D) to a glutamic acid (E) at the amino acid position of 92 in the protein PTEN.

[0156] In some embodiments, the cancer as described herein encompasses obtaining a cancer sample and conducting genomic profiling. In some embodiments, the methods described herein further comprise obtaining a cancer sample and subjecting the cancer sample to genomic profiling. In some embodiments, the method further comprises obtaining a cancer sample from the subject and subjecting the cancer sample to genomic profiling prior. In some embodiments, the method further comprises obtaining a cancer sample from the subject and subjecting the cancer sample to genomic profiling prior to administering an AKT1 selective inhibitor. In some embodiments, the identifying, selecting, or screening is conducted before administering an AKT1 selective inhibitor. In some embodiments, the method further comprises obtaining a cancer sample from the subject and subjecting the cancer sample to genomic profiling prior to administering Compound A, B, C, or D, or a pharmaceutically acceptable salt of any oneWSGR Docket No. 61402-725.601thereof. In some embodiments, the identifying, selecting, or screening is conducted before administering Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof. In some embodiments, the genomic profiling is whole exome sequencing. In some embodiments, the method further comprises obtaining a cancer sample from the subject and subjecting the cancer sample to genomic profiling prior to administering Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the identifying, selecting, or screening is conducted before administering Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the genomic profiling is whole exome sequencing. In some embodiments, the method further comprises administering a second agent, wherein the second agent is selected from a CDK2 inhibitor, a CDK4 / 6 inhibitor, an aromatase inhibitor, an antiandrogen, an androgen synthesis inhibitor, an mTOR inhibitor, a PI3Ka inhibitor, a PI3Ka mutant inhibitor, a gonadotropin-releasing hormone (GnRH) agonist, a selective estrogen receptor modulator (SERM), and a selective estrogen receptor degrader (SERD).

[0157] Methods of Treatment

[0158] In some aspects, the present disclosure provides methods of treating cancer comprising administering to a subject in need thereof an AKT1 selective inhibitor. In some embodiments, the method of treating cancer comprises administering to a subject in need thereof an AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the method of treating cancer comprises administering to a subject in need thereof Compound A or a pharmaceutically acceptable salt thereof.

[0159] Methods of treating cancer having at least one mutation in the PI3K / AKT / PTEN signaling pathway

[0160] In some aspects, the present disclosure provides methods of treating cancer having at least one mutation in the PI3K / AKT / PTEN signaling pathway comprising, administering to a subject in need thereof an AKT1 selective inhibitor. In some embodiments, the method of treating cancer having at least one mutation in the PI3K / AKT / PTEN signaling pathway comprising, administering to a subject in need thereof an AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A or a pharmaceutically acceptable saltWSGR Docket No. 61402-725.601thereof. In some embodiments, the method comprises identifying a subject with at least one mutation in the PI3K / AKT / PTEN signaling pathway. In some embodiments, the method comprises selecting a subject with at least one mutation in the PI3K / AKT / PTEN signaling pathway. In some embodiments, the method comprises screening to identify a subject with at least one mutation in the PI3K / AKT / PTEN signaling pathway.

[0161] In some aspects, the present disclosure provides methods of treating cancer comprising identifying a subject with at least one mutation in the PI3K / AKT / PTEN signaling pathway; and administering to the subject an AKT1 selective inhibitor. In some embodiments, the method of treating cancer comprises identifying a subject with at least one mutation in the PI3K / AKT / PTEN signaling pathway; and administering to the subject an AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound B or a pharmaceutically acceptable salt thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound C or a pharmaceutically acceptable salt thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound D or a pharmaceutically acceptable salt thereof.

[0162] In some aspects, the present disclosure provides methods of treating cancer comprising selecting a subject with at least one mutation in the PI3K / AKT / PTEN signaling pathway; and administering to the subject an AKT1 selective inhibitor. In some embodiments, the method of treating cancer comprises selecting a subject with at least one mutation in the PI3K / AKT / PTEN signaling pathway; and administering to the subject an AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound B or a pharmaceutically acceptable salt thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound C or a pharmaceutically acceptable salt thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound D or a pharmaceutically acceptable salt thereof.WSGR Docket No. 61402-725.601

[0163] In some aspects, the present disclosure provides methods of treating cancer comprising screening to identify a subject with at least one mutation in the PI3K / AKT / PTEN signaling pathway; and administering to the subject identified in the screen an AKT1 selective inhibitor. In some embodiments, the method of treating cancer comprises screening to identify a subject with at least one mutation in the PI3K / AKT / PTEN signaling pathway; and administering to the subject identified in the screen an AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound B or a pharmaceutically acceptable salt thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound C or a pharmaceutically acceptable salt thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound D or a pharmaceutically acceptable salt thereof.

[0164] In some aspects, the present disclosure provides methods of treating cancer having at least one mutation in the PI3K / AKT / PTEN signaling pathway comprising, administering to a subject in need thereof an AKT1 selective inhibitor, wherein the subject has a relapsed or refractory cancer after receiving at least one prior treatment. In some embodiments, the method of treating cancer having at least one mutation in the PI3K / AKT / PTEN signaling pathway comprises administering to a subject in need thereof an AKT1 selective inhibitor, wherein the subject has a relapsed cancer after receiving at least one prior treatment. In some embodiments, the method of treating cancer having at least one mutation in the PI3K / AKT / PTEN signaling pathway comprises administering to a subject in need thereof an AKT1 selective inhibitor, wherein the subject has a refractory cancer after receiving at least one prior treatment.

[0165] In some aspects, the present disclosure provides methods of treating cancer having at least one mutation in the PI3K / AKT / PTEN signaling pathway comprising, administering to a subject in need thereof Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof, wherein the subject has a relapsed or refractory cancer after receiving at least one prior treatment. In some embodiments, the method of treating cancer having at least one mutation in the PI3K / AKT / PTEN signaling pathway comprises administering to a subject in need thereof Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof, wherein the subject has a relapsed cancer after receiving at least one prior treatment. In some embodiments, the method of treating a cancer having at least one mutation in the PI3K / AKT / PTEN signaling pathway comprises administering to a subject in need thereofWSGR Docket No. 61402-725.601Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof, wherein the subject has a refractory cancer after receiving at least one prior treatment. In some embodiments, the at least one prior treatment comprises a CDK2 inhibitor, a CDK4 / 6 inhibitor, an aromatase inhibitor, an anti-androgen, an androgen synthesis inhibitor, an mTOR inhibitor, a PI3Ka inhibitor, a PI3Ka mutant inhibitor, a gonadotropin-releasing hormone (GnRH) agonist, a selective estrogen receptor modulator (SERM), and a selective estrogen receptor degrader (SERD), or a combination thereof. In some embodiments, the subject has been previously administered a selective estrogen receptor degrader (SERD), an aromatase inhibitor, a CDK4 / 6 inhibitor, an anti-androgen, or a combination thereof. In some embodiments, the at least one prior treatment is a standard of care treatment. In some embodiments, the at least one prior treatment is a standard of care treatment is a recognized standard for cancer treatment under the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology.

[0166] In some aspects, the present disclosure provides methods of treating cancer having at least one mutation in the PI3K / AKT / PTEN signaling pathway comprising, administering to a subject in need thereof Compound A or a pharmaceutically acceptable salt thereof, wherein the subject has a relapsed or refractory cancer after receiving at least one prior treatment. In some embodiments, the method of treating cancer having at least one mutation in the PI3K / AKT / PTEN signaling pathway comprises administering to a subject in need thereof Compound A or a pharmaceutically acceptable salt thereof, wherein the subject has a relapsed cancer after receiving at least one prior treatment. In some embodiments, the method of treating a cancer having at least one mutation in the PI3K / AKT / PTEN signaling pathway comprises administering to a subject in need thereof Compound A or a pharmaceutically acceptable salt thereof, wherein the subject has a refractory cancer after receiving at least one prior treatment. In some embodiments, the at least one prior treatment comprises a CDK2 inhibitor, a CDK4 / 6 inhibitor, an aromatase inhibitor, an anti-androgen, an androgen synthesis inhibitor, an mTOR inhibitor, a PI3Ka inhibitor, a PI3Ka mutant inhibitor, a gonadotropin-releasing hormone (GnRH) agonist, a selective estrogen receptor modulator (SERM), and a selective estrogen receptor degrader (SERD), or a combination thereof. In some embodiments, the subject has been previously administered a selective estrogen receptor degrader (SERD), an aromatase inhibitor, a CDK4 / 6 inhibitor, an anti -androgen, or a combination thereof. In some embodiments, the at least one prior treatment is a standard of care treatment. In some embodiments, the at least one prior treatment is a standard of care treatment is a recognized standard for cancer treatment under the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology.WSGR Docket No. 61402-725.601

[0167] In some aspects, the present disclosure provides methods of treating cancer having at least one mutation in the PI3K / AKT / PTEN signaling pathway comprising, administering to a subject in need thereof an AKT1 selective inhibitor, wherein the subject has been previously administered a selective estrogen receptor degrader (SERD). In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof. In some embodiments, the AKT1 selective inhibitor is Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the method of treating cancer having at least one mutation in the PI3K / AKT / PTEN signaling pathway comprises, administering to the subject in need thereof Compound A or a pharmaceutically acceptable salt thereof, wherein the subject has been previously administered a SERD.

[0168] In some aspects, the present disclosure provides methods of treating cancer having at least one mutation in the PI3K / AKT / PTEN signaling pathway comprising, administering to a subject in need thereof an AKT1 selective inhibitor, wherein the subject has been previously administered an aromatase inhibitor. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof. In some embodiments, the AKT1 selective inhibitor or a is Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the method of treating cancer having at least one mutation in the PI3K / AKT / PTEN signaling pathway comprises, administering to the subject in need thereof Compound A or a pharmaceutically acceptable salt thereof, wherein the subject has been previously administered an aromatase inhibitor. In some embodiments, the method of treating cancer having at least one mutation in the PI3K / AKT / PTEN signaling pathway comprises, administering to the subject in need thereof Compound B or a pharmaceutically acceptable salt thereof, wherein the subject has been previously administered an aromatase inhibitor. In some embodiments, the method of treating cancer having at least one mutation in the PI3K / AKT / PTEN signaling pathway comprises, administering to the subject in need thereof Compound C or a pharmaceutically acceptable salt thereof, wherein the subject has been previously administered an aromatase inhibitor. In some embodiments, the method of treating cancer having at least one mutation in the PI3K / AKT / PTEN signaling pathway comprises, administering to the subject in need thereof Compound D or a pharmaceutically acceptable salt thereof, wherein the subject has been previously administered an aromatase inhibitor.

[0169] In some aspects, the present disclosure provides methods of treating cancer having at least one mutation in the PI3K / AKT / PTEN signaling pathway comprising, administering to a subject in need thereof an AKT1 selective inhibitor, wherein the subject has been previouslyWSGR Docket No. 61402-725.601administered a CDK2inhibitor. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof. In some embodiments, the AKT1 selective inhibitor is Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the method of treating cancer having at least one mutation in the PI3K / AKT / PTEN signaling pathway comprises, administering to the subject in need thereof Compound A or a pharmaceutically acceptable salt thereof, wherein the subject has been previously administered a CDK2 inhibitor. In some embodiments, the method of treating cancer having at least one mutation in the PI3K / AKT / PTEN signaling pathway comprises, administering to the subject in need thereof Compound B or a pharmaceutically acceptable salt thereof, wherein the subject has been previously administered a CDK2 inhibitor. In some embodiments, the method of treating cancer having at least one mutation in the PI3K / AKT / PTEN signaling pathway comprises, administering to the subject in need thereof Compound C or a pharmaceutically acceptable salt thereof, wherein the subject has been previously administered a CDK2 inhibitor. In some embodiments, the method of treating cancer having at least one mutation in the PI3K / AKT / PTEN signaling pathway comprises, administering to the subject in need thereof Compound D or a pharmaceutically acceptable salt thereof, wherein the subject has been previously administered a CDK2 inhibitor.

[0170] In some aspects, the present disclosure provides methods of treating cancer having at least one mutation in the PI3K / AKT / PTEN signaling pathway comprising, administering to a subject in need thereof an AKT1 selective inhibitor, wherein the subject has been previously administered a CDK4 / 6 inhibitor. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof. In some embodiments, the AKT1 selective inhibitor is Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the method of treating cancer having at least one mutation in the PI3K / AKT / PTEN signaling pathway comprises, administering to the subject in need thereof Compound A or a pharmaceutically acceptable salt thereof, wherein the subject has been previously administered a CDK4 / 6 inhibitor. In some embodiments, the method of treating cancer having at least one mutation in the PI3K / AKT / PTEN signaling pathway comprises, administering to the subject in need thereof Compound B or a pharmaceutically acceptable salt thereof, wherein the subject has been previously administered a CDK4 / 6 inhibitor. In some embodiments, the method of treating cancer having at least one mutation in the PI3K / AKT / PTEN signaling pathway comprises, administering to the subject in need thereof Compound C or a pharmaceutically acceptable salt thereof, wherein the subject has been previously administered a CDK4 / 6 inhibitor. In someWSGR Docket No. 61402-725.601embodiments, the method of treating cancer having at least one mutation in the PI3K / AKT / PTEN signaling pathway comprises, administering to the subject in need thereof Compound D or a pharmaceutically acceptable salt thereof, wherein the subject has been previously administered a CDK4 / 6 inhibitor.

[0171] In some aspects, the present disclosure provides methods of treating cancer having at least one mutation in the PI3K / AKT / PTEN signaling pathway comprising, administering to a subject in need thereof an AKT1 selective inhibitor, wherein the subject has been previously administered an anti -androgen. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof. In some embodiments, the AKT1 selective inhibitor is Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the method of treating cancer having at least one mutation in the PI3K / AKT / PTEN signaling pathway comprises, administering to the subject in need thereof Compound A or a pharmaceutically acceptable salt thereof, wherein the subject has been previously administered an anti-androgen.

[0172] In some aspects, the present disclosure provides methods of treating cancer having at least one mutation in the PI3K / AKT / PTEN signaling pathway comprising, administering to a subject in need thereof an AKT1 selective inhibitor, wherein the subject has been previously administered a selective estrogen receptor degrader (SERD) and a CDK4 / 6 inhibitor. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof. In some embodiments, the AKT1 selective inhibitor is Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the method of treating cancer having at least one mutation in the PI3K / AKT / PTEN signaling pathway comprises, administering to the subject in need thereof Compound A or a pharmaceutically acceptable salt thereof, wherein the subject has been previously administered a SERD and a CDK4 / 6 inhibitor.

[0173] In some aspects, the present disclosure provides methods of treating cancer having at least one mutation in the PI3K / AKT / PTEN signaling pathway comprising, administering to a subject in need thereof an AKT1 selective inhibitor, wherein the subject has been previously administered an aromatase inhibitor and a CDK4 / 6 inhibitor. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof. In some embodiments, the AKT1 selective inhibitor is Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the method of treating cancer having at least one mutation in the PI3K / AKT / PTEN signaling pathway comprises, administering to the subject in need thereof Compound A or aWSGR Docket No. 61402-725.601pharmaceutically acceptable salt thereof, wherein the subject has been previously administered an aromatase inhibitor and a CDK4 / 6 inhibitor.

[0174] In some aspects, the present disclosure provides methods of treating cancer having at least one mutation in the PI3K / AKT / PTEN signaling pathway comprising, administering to a subject in need thereof an AKT1 selective inhibitor and a second agent selected from a CDK2 inhibitor, a CDK4 / 6 inhibitor, an aromatase inhibitor, an anti -androgen, an androgen synthesis inhibitor, an mTOR inhibitor, a PI3Ka inhibitor, a PI3Ka mutant inhibitor, a gonadotropin-releasing hormone (GnRH) agonist, a selective estrogen receptor modulator (SERM), and a selective estrogen receptor degrader (SERD). In some embodiments, the subject is a second agent selected from a CDK2 inhibitor, a CDK4 / 6 inhibitor, an aromatase inhibitor, an anti-androgen, an androgen synthesis inhibitor, an mTOR inhibitor, a PI3Ka inhibitor, a PI3Ka mutant inhibitor, a gonadotropin-releasing hormone (GnRH) agonist, a selective estrogen receptor modulator (SERM), and a selective estrogen receptor degrader (SERD). In some embodiments, the second agent is a CDK2 inhibitor. In some embodiments, the second agent is a CDK4 / 6 inhibitor. In some embodiments, the second agent is an aromatase inhibitor. In some embodiments, the second agent is an anti-androgen. In some embodiments, the second agent is an androgen synthesis inhibitor. In some embodiments, the second agent is an mTOR inhibitor. the second agent is a PI3Kα inhibitor. In some embodiments, the second agent is a PI3Ka mutant inhibitor. In some embodiments, the second agent is a gonadotropin-releasing hormone (GnRH) agonist. In some embodiments, the second agent is a selective estrogen receptor modulator (SERM). In some embodiments, the second agent is a selective estrogen receptor degrader (SERD).

[0175] In some embodiments, the method of treating cancer having at least one mutation in the PI3K / AKT / PTEN signaling pathway comprises, administering to a subject in need thereof Compound A, B, C, or D, and a second agent selected from a CDK2 inhibitor, a CDK4 / 6 inhibitor, an aromatase inhibitor, an anti-androgen, an androgen synthesis inhibitor, an mTOR inhibitor, a PI3Ka inhibitor, a PI3Ka mutant inhibitor, a gonadotropin-releasing hormone (GnRH) agonist, a selective estrogen receptor modulator (SERM), a selective estrogen receptor degrader (SERD). In some embodiments, the method of treating cancer having at least one mutation in the PI3K / AKT / PTEN signaling pathway comprises, administering to a subject in need thereof Compound A and a second agent selected from a CDK2 inhibitor, a CDK4 / 6 inhibitor, an aromatase inhibitor, an anti-androgen, an androgen synthesis inhibitor, an mTOR inhibitor, a PI3Ka inhibitor, a PI3Ka mutant inhibitor, a gonadotropin-releasing hormone (GnRH) agonist, a selective estrogen receptor modulator (SERM), a selective estrogen receptor degrader (SERD). In some embodiments, the second agent is a CDK2 inhibitor. In someWSGR Docket No. 61402-725.601embodiments, the second agent is a CDK4 / 6 inhibitor. In some embodiments, the second agent is an aromatase inhibitor. In some embodiments, the second agent is an anti-androgen. In some embodiments, the second agent is an androgen synthesis inhibitor. In some embodiments, the second agent is an mTOR inhibitor. In some embodiments, the second agent is a PI3Ka inhibitor. In some embodiments, the second agent is a PI3Ka mutant inhibitor. In some embodiments, the second agent is a gonadotropin-releasing hormone (GnRH) agonist. In some embodiments, the second agent is a selective estrogen receptor modulator (SERM). In some embodiments, the second agent is a selective estrogen receptor degrader (SERD).

[0176] In some aspects, the present disclosure provides methods of treating cancer having at least one mutation in the PI3K / AKT / PTEN signaling pathway comprising, administering to a subject in need thereof Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof. In some embodiments, the method of treating cancer having at least one mutation in the PI3K / AKT / PTEN signaling pathway comprises identifying a subject with at least one mutation in the PI3K / AKT / PTEN signaling pathway; and administering to the subject in need thereof Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof. In some embodiments, the method of treating cancer having at least one mutation in the PI3K / AKT / PTEN signaling pathway comprises selecting a subject with at least one mutation in the PI3K / AKT / PTEN signaling pathway; and administering to the subject in need thereof Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof. In some embodiments, the method of treating cancer having at least one mutation in the PI3K / AKT / PTEN signaling pathway comprises screening to identify a subject with at least one mutation in the PI3K / AKT / PTEN signaling pathway; and administering to the subject in need thereof Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof.

[0177] In some aspects, the present disclosure provides methods of treating cancer having at least one mutation in the PI3K / AKT / PTEN signaling pathway comprising, administering to a subject in need thereof Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the method of treating cancer having at least one mutation in the PI3K / AKT / PTEN signaling pathway comprises identifying a subject with at least one mutation in the PI3K / AKT / PTEN signaling pathway; and administering to the subject in need thereof Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the method of treating cancer having at least one mutation in the PI3K / AKT / PTEN signaling pathway comprises selecting a subject with at least one mutation in the PI3K / AKT / PTEN signaling pathway; and administering to the subject in need thereof Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the method of treating cancer having at least one mutation in the PI3K / AKT / PTEN signaling pathway comprises screening to identify a subjectWSGR Docket No. 61402-725.601with at least one mutation in the PI3K / AKT / PTEN signaling pathway; and administering to the subject in need thereof Compound A or a pharmaceutically acceptable salt thereof.

[0178] In some embodiments, the subject has a relapsed or refractory cancer after receiving at least one prior treatment. In some embodiments, the subject has a relapsed cancer after receiving at least one prior treatment. In some embodiments, the subject has a refractory cancer after receiving at least one prior treatment. In some embodiments, the at least one prior treatment comprises from a CDK2 inhibitor, a CDK4 / 6 inhibitor, an aromatase inhibitor, an anti-androgen, an androgen synthesis inhibitor, an mTOR inhibitor, a PI3Kα inhibitor, a PI3Kα mutant inhibitor, a gonadotropin-releasing hormone (GnRH) agonist, a selective estrogen receptor modulator (SERM), a selective estrogen receptor degrader (SERD), or a combination thereof. In some embodiments, the at least one prior treatment is selected from surgery, radiation, chemotherapy, and a combination thereof. In some embodiments, the at least one prior treatment is selected from surgery, radiation, and chemotherapy.

[0179] In some embodiments, the at least one prior treatment is radiation.

[0180] In some embodiments, the at least one prior treatment is chemotherapy. In some embodiments, the chemotherapy is selected from a platinum-based chemotherapy, a poly-ADP-ribose polymerase (PARP) inhibitor, a CDK4 / 6 inhibitor, an aromatase inhibitor, an antiandrogen, an androgen synthesis inhibitor, an mTOR inhibitor, a PI3Kα inhibitor, a PI3Kα mutant inhibitor, a gonadotropin-releasing hormone (GnRH) agonist, a selective estrogen receptor modulator (SERM), and a selective estrogen receptor degrader (SERD). In some embodiments, the chemotherapy is selected from a CDK2 inhibitor, a CDK4 / 6 inhibitor, an aromatase inhibitor, an anti-androgen, an androgen synthesis inhibitor, an mTOR inhibitor, a PI3Kα inhibitor, a PI3Kα mutant inhibitor, a gonadotropin-releasing hormone (GnRH) agonist, a selective estrogen receptor modulator (SERM), a selective estrogen receptor degrader (SERD, and a combination thereof. In some embodiments, the chemotherapy is selected from a CDK2 inhibitor, a CDK4 / 6 inhibitor, an aromatase inhibitor, an anti-androgen, and a selective estrogen receptor degrader (SERD). In some embodiments, the chemotherapy is a CDK2 inhibitor. In some embodiments, the chemotherapy is a CDK4 / 6 inhibitor. In some embodiments, the chemotherapy is an aromatase inhibitor. In some embodiments, the chemotherapy is an antiandrogen. In some embodiments, the chemotherapy is a selective estrogen receptor degrader (SERD). In some embodiments, the chemotherapy is a platinum-based chemotherapy. In some embodiments, the chemotherapy is a poly-ADP-ribose polymerase (PARP) inhibitor.

[0181] In some embodiments, the at least one prior treatment is surgery. In some embodiments, the surgery is a complete resection or a partial resection. In some embodiments, the surgery is a complete resection. In some embodiments, the surgery is a partial resection.WSGR Docket No. 61402-725.601

[0182] In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is selected from breast cancer, kidney cancer, prostate cancer, head and neck cancer, gastric cancer, lung cancer, endometrial cancer, ovarian cancer, cervical cancer, esophageal cancer, and colon cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the breast cancer is ER+ / HER2- breast cancer. In some embodiments, the breast cancer is triple negative breast cancer. In some embodiments, the cancer is kidney cancer. In some embodiments, the kidney cancer is renal cell carcinoma. In some embodiments, the cancer is prostate cancer. In some embodiments, the prostate cancer is castration resistant prostate cancer. In some embodiments, the cancer is head and neck cancer. In some embodiments, the head and neck cancer is head and neck squamous cell carcinoma. In some embodiments, the cancer is gastric cancer. In some embodiments, the cancer is lung cancer. In some embodiments, the lung cancer is squamous cell lung cancer. In some embodiments, the cancer is endometrial cancer. In some embodiments, the cancer is colon cancer. In some embodiments, the colon cancer is colorectal cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is cervical cancer. In some embodiments, the cancer is esophageal cancer. In some embodiments, the esophageal cancer is squamous cell esophageal cancer.

[0183] Methods of treating a PTEN loss of function cancer

[0184] In some aspects, the present disclosure provides methods of treating a PTEN loss of function cancer comprising, administering to a subject in need thereof an AKT1 selective inhibitor. In some embodiments, the method of treating a PTEN loss of function cancer comprises, administering to a subject in need thereof an AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the method comprises identifying a subject with a PTEN loss of function cancer. In some embodiments, the method comprises selecting a subject with a PTEN loss of function cancer. In some embodiments, the method comprises screening to identify a subject with a PTEN loss of function cancer.

[0185] In some aspects, the present disclosure provides methods of treating cancer comprising identifying a subject with a PTEN loss of function cancer; and administering to the subject an AKT1 selective inhibitor. In some embodiments, the present disclosure provides methods of treating cancer comprising identifying a subject with a PTEN loss of function cancer; and administering to the subject an AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptableWSGR Docket No. 61402-725.601salt thereof is Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A or a pharmaceutically acceptable salt thereof.

[0186] In some aspects, the present disclosure provides methods of treating cancer comprising selecting a subject with a PTEN loss of function cancer; and administering to the subject an AKT1 selective inhibitor. In some embodiments, the present disclosure provides methods of treating cancer comprising selecting a subject with a PTEN loss of function cancer; and administering to the subject an AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound B or a pharmaceutically acceptable salt thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound C or a pharmaceutically acceptable salt thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound D or a pharmaceutically acceptable salt thereof.

[0187] In some aspects, the present disclosure provides methods of treating cancer comprising screening to identify a subject with a PTEN loss of function cancer; and administering to the subject identified in the screen an AKT1 selective inhibitor. In some embodiments, the present disclosure provides methods of treating cancer comprising screening to identify a subject with a PTEN loss of function cancer; and administering to the subject identified in the screen an AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound B or a pharmaceutically acceptable salt thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound C or a pharmaceutically acceptable salt thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound D or a pharmaceutically acceptable salt thereof.

[0188] In some aspects, the present disclosure provides methods of treating a PTEN loss of function cancer comprising, administering to a subject in need thereof an AKT1 selective inhibitor, wherein the subject has a relapsed or refractory cancer after receiving at least one priorWSGR Docket No. 61402-725.601treatment. In some embodiments, the method of treating a PTEN loss of function cancer comprises, administering to a subject in need thereof an AKT1 selective inhibitor, wherein the subject has a relapsed cancer after receiving at least one prior treatment. In some embodiments, the method of treating a PTEN loss of function cancer comprises, administering to a subject in need thereof an AKT1 selective inhibitor, wherein the subject has a refractory cancer after receiving at least one prior treatment.

[0189] In some aspects, the present disclosure provides methods of treating a PTEN loss of function cancer comprising, administering to a subject in need thereof Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof, wherein the subject has a relapsed or refractory cancer after receiving at least one prior treatment. In some embodiments, the method of treating a PTEN loss of function cancer comprises, administering to a subject in need thereof Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof, wherein the subject has a relapsed cancer after receiving at least one prior treatment. In some embodiments, the method of treating a PTEN loss of function cancer comprises, administering to a subject in need thereof Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof, wherein the subject has a refractory cancer after receiving at least one prior treatment.

[0190] In some aspects, the present disclosure provides methods of treating a PTEN loss of function cancer comprising, administering to a subject in need thereof Compound A or a pharmaceutically acceptable salt thereof, wherein the subject has a relapsed or refractory cancer after receiving at least one prior treatment. In some embodiments, the method of treating a PTEN loss of function cancer comprises, administering to a subject in need thereof Compound A or a pharmaceutically acceptable salt thereof, wherein the subject has a relapsed cancer after receiving at least one prior treatment. In some embodiments, the method of treating a PTEN loss of function cancer comprises, administering to a subject in need thereof Compound A or a pharmaceutically acceptable salt thereof, wherein the subject has a refractory cancer after receiving at least one prior treatment.

[0191] In some embodiments, the at least one prior treatment comprises a selective estrogen receptor degrader (SERD), an aromatase inhibitor, a CDK4 / 6 inhibitor, an anti-androgen, or a combination thereof. In some embodiments, the subject has been previously administered a selective estrogen receptor degrader (SERD), an aromatase inhibitor, a CDK4 / 6 inhibitor, an anti-androgen, or a combination thereof. In some embodiments, the at least one prior treatment is a standard of care treatment. In some embodiments, the standard of care treatment is a recognized standard for cancer treatment under the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology.WSGR Docket No. 61402-725.601

[0192] In some aspects, the present disclosure provides methods of treating a PTEN loss of function cancer comprising, administering to a subject in need thereof an AKT1 selective inhibitor, wherein the subject has been previously administered a selective estrogen receptor degrader (SERD). In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides methods of treating a PTEN loss of function cancer comprising, administering to the subject in need thereof Compound A or a pharmaceutically acceptable salt thereof, wherein the subject has been previously administered a SERD.

[0193] In some aspects, the present disclosure provides methods of treating a PTEN loss of function cancer comprising, administering to a subject in need thereof an AKT1 selective inhibitor, wherein the subject has been previously administered an aromatase inhibitor. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound B or a pharmaceutically acceptable salt thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound C or a pharmaceutically acceptable salt thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound D or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides methods of treating a PTEN loss of function cancer comprising, administering to the subject in need thereof Compound A or a pharmaceutically acceptable salt thereof, wherein the subject has been previously administered an aromatase inhibitor.

[0194] In some aspects, the present disclosure provides methods of treating a PTEN loss of function cancer comprising, administering to a subject in need thereof an AKT1 selective inhibitor, wherein the subject has been previously administered a CDK2 inhibitor. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound B or a pharmaceutically acceptable salt thereof. In some embodiments, the AKT1 selective inhibitor orWSGR Docket No. 61402-725.601a pharmaceutically acceptable salt thereof is Compound C or a pharmaceutically acceptable salt thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound D or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides methods of treating a PTEN loss of function cancer comprising, administering to the subject in need thereof Compound A or a pharmaceutically acceptable salt thereof, wherein the subject has been previously administered a CDK2 inhibitor.

[0195] In some aspects, the present disclosure provides methods of treating a PTEN loss of function cancer comprising, administering to a subject in need thereof an AKT1 selective inhibitor, wherein the subject has been previously administered a CDK4 / 6 inhibitor. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound B or a pharmaceutically acceptable salt thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound C or a pharmaceutically acceptable salt thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound D or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides methods of treating a PTEN loss of function cancer comprising, administering to the subject in need thereof Compound A or a pharmaceutically acceptable salt thereof, wherein the subject has been previously administered a CDK4 / 6 inhibitor.

[0196] In some aspects, the present disclosure provides methods of treating a PTEN loss of function cancer comprising, administering to a subject in need thereof an AKT1 selective inhibitor, wherein the subject has been previously administered an anti -androgen. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound B or a pharmaceutically acceptable salt thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound C or a pharmaceutically acceptable salt thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound D or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides methods of treating a PTEN loss of function cancer comprising,WSGR Docket No. 61402-725.601administering to the subject in need thereof Compound A or a pharmaceutically acceptable salt thereof, wherein the subject has been previously administered an anti-androgen.

[0197] In some aspects, the present disclosure provides methods of treating a PTEN loss of function cancer comprising, administering to a subject in need thereof an AKT1 selective inhibitor, wherein the subject has been previously administered a selective estrogen receptor degrader (SERD) and a CDK4 / 6 inhibitor. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound B or a pharmaceutically acceptable salt thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound C or a pharmaceutically acceptable salt thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound D or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides methods of treating a PTEN loss of function cancer comprising, administering to the subject in need thereof Compound A or a pharmaceutically acceptable salt thereof, wherein the subject has been previously administered a SERD and a CDK4 / 6 inhibitor.

[0198] In some aspects, the present disclosure provides methods of treating a PTEN loss of function cancer comprising, administering to a subject in need thereof an AKT1 selective inhibitor, wherein the subject has been previously administered an aromatase inhibitor and a CDK4 / 6 inhibitor. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound B or a pharmaceutically acceptable salt thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound C or a pharmaceutically acceptable salt thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound D or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides methods of treating a PTEN loss of function cancer comprising, administering to the subject in need thereof Compound A or a pharmaceutically acceptable salt thereof, wherein the subject has been previously administered an aromatase inhibitor and a CDK4 / 6 inhibitor.WSGR Docket No. 61402-725.601

[0199] In some embodiments, the method of treating a PTEN loss of function cancer comprises, administering to a subject in need thereof an AKT1 selective inhibitor and a second agent selected from a CDK2 inhibitor, a CDK4 / 6 inhibitor, an aromatase inhibitor, an anti -androgen, an androgen synthesis inhibitor, an mTOR inhibitor, a PI3Ka inhibitor, a PI3Ka mutant inhibitor, a gonadotropin-releasing hormone (GnRH) agonist, a selective estrogen receptor modulator (SERM), and a selective estrogen receptor degrader (SERD). In some embodiments, the subject is a second agent selected from a CDK2 inhibitor, a CDK4 / 6 inhibitor, an aromatase inhibitor, an anti-androgen, an androgen synthesis inhibitor, an mTOR inhibitor, a PI3Ka inhibitor, a PI3Ka mutant inhibitor, a gonadotropin-releasing hormone (GnRH) agonist, a selective estrogen receptor modulator (SERM), and a selective estrogen receptor degrader (SERD). In some embodiments, the second agent is a CDK2 inhibitor. In some embodiments, the second agent is a CDK4 / 6 inhibitor. In some embodiments, the second agent is an aromatase inhibitor. In some embodiments, the second agent is an anti-androgen. In some embodiments, the second agent is an androgen synthesis inhibitor. In some embodiments, the second agent is an mTOR inhibitor. the second agent is a PI3Kα inhibitor. In some embodiments, the second agent is a PI3Ka mutant inhibitor. In some embodiments, the second agent is a gonadotropin-releasing hormone (GnRH) agonist. In some embodiments, the second agent is a selective estrogen receptor modulator (SERM). In some embodiments, the second agent is a selective estrogen receptor degrader (SERD).

[0200] In some embodiments, the method of treating a PTEN loss of function cancer comprises, administering to a subject in need thereof Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof and a second agent selected from a CDK2 inhibitor, a CDK4 / 6 inhibitor, an aromatase inhibitor, an anti-androgen, an androgen synthesis inhibitor, an mTOR inhibitor, a PI3Kα inhibitor, a PI3Kα mutant inhibitor, a gonadotropin-releasing hormone (GnRH) agonist, a selective estrogen receptor modulator (SERM), and a selective estrogen receptor degrader (SERD). In some embodiments, the method of treating a PTEN loss of function cancer comprises, administering to a subject in need thereof Compound A or pharmaceutically acceptable salt thereof and a second agent selected from a CDK2 inhibitor, a CDK4 / 6 inhibitor, an aromatase inhibitor, an anti-androgen, an androgen synthesis inhibitor, an mTOR inhibitor, a PI3Kα inhibitor, a PI3Kα mutant inhibitor, a gonadotropin-releasing hormone (GnRH) agonist, a selective estrogen receptor modulator (SERM), and a selective estrogen receptor degrader (SERD). In some embodiments, the subject is a second agent selected from a CDK2 inhibitor, a CDK4 / 6 inhibitor, an aromatase inhibitor, an anti-androgen, an androgen synthesis inhibitor, an mTOR inhibitor, a PI3Kα inhibitor, a PI3Kα mutant inhibitor, a gonadotropin-releasing hormone (GnRH) agonist, a selective estrogen receptor modulatorWSGR Docket No. 61402-725.601(SERM), and a selective estrogen receptor degrader (SERD). In some embodiments, the second agent is a CDK2 inhibitor. In some embodiments, the second agent is a CDK4 / 6 inhibitor. In some embodiments, the second agent is an aromatase inhibitor. In some embodiments, the second agent is an anti-androgen. In some embodiments, the second agent is an androgen synthesis inhibitor. In some embodiments, the second agent is an mTOR inhibitor. the second agent is a PI3Kα inhibitor. In some embodiments, the second agent is a PI3Ka mutant inhibitor. In some embodiments, the second agent is a gonadotropin-releasing hormone (GnRH) agonist. In some embodiments, the second agent is a selective estrogen receptor modulator (SERM). In some embodiments, the second agent is a selective estrogen receptor degrader (SERD).

[0201] In some aspects, the present disclosure provides methods of treating a PTEN loss of function cancer comprising, administering to the subject in need thereof Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof. In some embodiments, the present disclosure provides methods of treating cancer comprising identifying a subject with a PTEN loss of function cancer; and administering to the subject in need thereof Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof. In some embodiments, the present disclosure provides methods of treating cancer comprising selecting a subject with a PTEN loss of function cancer; and administering to the subject in need thereof Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof. In some embodiments, the present disclosure provides methods of treating cancer comprising screening to identify a subject with a PTEN loss of function cancer; and administering to the subject in need thereof Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof.

[0202] In some aspects, the present disclosure provides methods of treating a PTEN loss of function cancer comprising, administering to the subject in need thereof Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides methods of treating cancer comprising identifying a subject with a PTEN loss of function cancer; and administering to the subject in need thereof Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides methods of treating cancer comprising selecting a subject with a PTEN loss of function cancer; and administering to the subject in need thereof Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides methods of treating cancer comprising screening to identify a subject with a PTEN loss of function cancer; and administering to the subject in need thereof Compound A or a pharmaceutically acceptable salt thereof.

[0203] In some embodiments, the subject has a relapsed or refractory cancer after receiving at least one prior treatment. In some embodiments, the subject has a relapsed cancer after receivingWSGR Docket No. 61402-725.601at least one prior treatment. In some embodiments, the subject has a refractory cancer after receiving at least one prior treatment. In some embodiments, the at least one prior treatment comprises from a CDK2 inhibitor, a CDK4 / 6 inhibitor, an aromatase inhibitor, an anti-androgen, an androgen synthesis inhibitor, an mTOR inhibitor, a PI3Kα inhibitor, a PI3Kα mutant inhibitor, a gonadotropin-releasing hormone (GnRH) agonist, a selective estrogen receptor modulator (SERM), a selective estrogen receptor degrader (SERD), or a combination thereof. In some embodiments, the at least one prior treatment is selected from surgery, radiation, chemotherapy, and a combination thereof. In some embodiments, the at least one prior treatment is selected from surgery, radiation, and chemotherapy.

[0204] In some embodiments, the at least one prior treatment is radiation.

[0205] In some embodiments, the at least one prior treatment is chemotherapy. In some embodiments, the chemotherapy is selected from a platinum-based chemotherapy, a poly-ADP-ribose polymerase (PARP) inhibitor, a CDK2 inhibitor, a CDK4 / 6 inhibitor, an aromatase inhibitor, an anti-androgen, an androgen synthesis inhibitor, an mTOR inhibitor, a PI3Kα inhibitor, a PI3Kα mutant inhibitor, a gonadotropin-releasing hormone (GnRH) agonist, a selective estrogen receptor modulator (SERM), and a selective estrogen receptor degrader (SERD). In some embodiments, the chemotherapy is selected from a CDK2 inhibitor, a CDK4 / 6 inhibitor, an aromatase inhibitor, an anti-androgen, an androgen synthesis inhibitor, an mTOR inhibitor, a PI3Kα inhibitor, a PI3Kα mutant inhibitor, a gonadotropin-releasing hormone (GnRH) agonist, a selective estrogen receptor modulator (SERM), a selective estrogen receptor degrader (SERD, and a combination thereof. In some embodiments, the chemotherapy is selected from a CDK2 inhibitor, a CDK4 / 6 inhibitor, an aromatase inhibitor, an anti-androgen, and a selective estrogen receptor degrader (SERD). In some embodiments, the chemotherapy is a CDK2 inhibitor. In some embodiments, the chemotherapy is a CDK4 / 6 inhibitor. In some embodiments, the chemotherapy is an aromatase inhibitor. In some embodiments, the chemotherapy is an anti-androgen. In some embodiments, the chemotherapy is a selective estrogen receptor degrader (SERD). In some embodiments, the chemotherapy is a platinumbased chemotherapy. In some embodiments, the chemotherapy is a poly-ADP-ribose polymerase (PARP) inhibitor.

[0206] In some embodiments, the at least one prior treatment is surgery. In some embodiments, the surgery is a complete resection or a partial resection. In some embodiments, the surgery is a complete resection. In some embodiments, the surgery is a partial resection.

[0207] In some embodiments, the PTEN loss of function cancer is a solid tumor. In some embodiments, the PTEN loss of function cancer is selected from breast cancer, kidney cancer, prostate cancer, head and neck cancer, gastric cancer, lung cancer, endometrial cancer, ovarianWSGR Docket No. 61402-725.601cancer, cervical cancer, esophageal cancer, and colon cancer. In some embodiments, the PTEN loss of function cancer is breast cancer. In some embodiments, the breast cancer is ER+ / HER2-breast cancer. In some embodiments, the breast cancer is triple negative breast cancer. In some embodiments, the PTEN loss of function cancer is kidney cancer. In some embodiments, the kidney cancer is renal cell carcinoma. In some embodiments, the PTEN loss of function cancer is prostate cancer. In some embodiments, the prostate cancer is castration resistant prostate cancer. In some embodiments, the PTEN loss of function cancer is head and neck cancer. In some embodiments, the head and neck cancer is head and neck squamous cell carcinoma. In some embodiments, the PTEN loss of function cancer is gastric cancer. In some embodiments, the PTEN loss of function cancer is lung cancer. In some embodiments, the lung cancer is squamous cell lung cancer. In some embodiments, the PTEN loss of function cancer is endometrial cancer. In some embodiments, the PTEN loss of function cancer is colon cancer. In some embodiments, the colon cancer is colorectal cancer. In some embodiments, the PTEN loss of function cancer is ovarian cancer. In some embodiments, the PTEN loss of function cancer is cervical cancer. In some embodiments, the PTEN loss of function cancer is esophageal cancer. In some embodiments, the esophageal cancer is squamous cell esophageal cancer.

[0208] Methods of treating a PTEN deficient cancer

[0209] In some aspects, the present disclosure provides methods of treating a PTEN deficient cancer comprising, administering to a subject in need thereof an AKT1 selective inhibitor. In some embodiments, the method of treating a PTEN deficient cancer comprises, administering to a subject in need thereof an AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the method comprises identifying a subject with a PTEN deficient cancer. In some embodiments, the method comprises selecting a subject with a PTEN deficient cancer. In some embodiments, the method comprises screening to identify a subject with a PTEN deficient cancer.

[0210] In some aspects, the present disclosure provides methods of treating cancer comprising identifying a subject with a PTEN deficient cancer; and administering to the subject an AKT1 selective inhibitor. In some embodiments, the present disclosure provides methods of treating cancer comprising identifying a subject with a PTEN deficient cancer; and administering to the subject an AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof. In someWSGR Docket No. 61402-725.601embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A or a pharmaceutically acceptable salt thereof.

[0211] In some aspects, the present disclosure provides methods of treating cancer comprising selecting a subject with a PTEN deficient cancer; and administering to the subject an AKT1 selective inhibitor. In some embodiments, the present disclosure provides methods of treating cancer comprising selecting a subject with a PTEN deficient cancer; and administering to the subject an AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound B or a pharmaceutically acceptable salt thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound C or a pharmaceutically acceptable salt thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound D or a pharmaceutically acceptable salt thereof.

[0212] In some aspects, the present disclosure provides methods of treating cancer comprising screening to identify a subject with a PTEN deficient cancer; and administering to the subject identified in the screen an AKT1 selective inhibitor. In some embodiments, the present disclosure provides methods of treating cancer comprising screening to identify a subject with a PTEN deficient cancer; and administering to the subject identified in the screen an AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound B or a pharmaceutically acceptable salt thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound C or a pharmaceutically acceptable salt thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound D or a pharmaceutically acceptable salt thereof.

[0213] In some aspects, the present disclosure provides methods of treating a PTEN deficient cancer comprising, administering to a subject in need thereof an AKT1 selective inhibitor, wherein the subject has a relapsed or refractory cancer after receiving at least one prior treatment. In some embodiments, the method of treating a PTEN deficient cancer comprises,WSGR Docket No. 61402-725.601administering to a subject in need thereof an AKT1 selective inhibitor, wherein the subject has a relapsed cancer after receiving at least one prior treatment. In some embodiments, the method of treating a PTEN deficient cancer comprises, administering to a subject in need thereof an AKT1 selective inhibitor, wherein the subject has a refractory cancer after receiving at least one prior treatment.

[0214] In some aspects, the present disclosure provides methods of treating a PTEN deficient cancer comprising, administering to a subject in need thereof Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof, wherein the subject has a relapsed or refractory cancer after receiving at least one prior treatment. In some embodiments, the method of treating a PTEN deficient cancer comprises, administering to a subject in need thereof Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof, wherein the subject has a relapsed cancer after receiving at least one prior treatment. In some embodiments, the method of treating a PTEN deficient cancer comprises, administering to a subject in need thereof Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof, wherein the subject has a refractory cancer after receiving at least one prior treatment.

[0215] In some aspects, the present disclosure provides methods of treating a PTEN deficient cancer comprising, administering to a subject in need thereof Compound A or a pharmaceutically acceptable salt thereof, wherein the subject has a relapsed or refractory cancer after receiving at least one prior treatment. In some embodiments, the method of treating a PTEN deficient cancer comprises, administering to a subject in need thereof Compound A or a pharmaceutically acceptable salt thereof, wherein the subject has a relapsed cancer after receiving at least one prior treatment. In some embodiments, the method of treating a PTEN deficient cancer comprises, administering to a subject in need thereof Compound A or a pharmaceutically acceptable salt thereof, wherein the subject has a refractory cancer after receiving at least one prior treatment.

[0216] In some embodiments, the at least one prior treatment comprises a selective estrogen receptor degrader (SERD), an aromatase inhibitor, a CDK4 / 6 inhibitor, an anti-androgen, or a combination thereof. In some embodiments, the subject has been previously administered a selective estrogen receptor degrader (SERD), an aromatase inhibitor, a CDK4 / 6 inhibitor, an anti-androgen, or a combination thereof. In some embodiments, the at least one prior treatment is a standard of care treatment. In some embodiments, the standard of care treatment is a recognized standard for cancer treatment under the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology.

[0217] In some aspects, the present disclosure provides methods of treating a PTEN deficient cancer comprising, administering to a subject in need thereof an AKT1 selective inhibitor,WSGR Docket No. 61402-725.601wherein the subject has been previously administered a selective estrogen receptor degrader (SERD). In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides methods of treating a PTEN deficient cancer comprising, administering to the subject in need thereof Compound A or a pharmaceutically acceptable salt thereof, wherein the subject has been previously administered a SERD.

[0218] In some aspects, the present disclosure provides methods of treating a PTEN deficient cancer comprising, administering to a subject in need thereof an AKT1 selective inhibitor, wherein the subject has been previously administered an aromatase inhibitor. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound B or a pharmaceutically acceptable salt thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound C or a pharmaceutically acceptable salt thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound D or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides methods of treating a PTEN deficient cancer comprising, administering to the subject in need thereof Compound A or a pharmaceutically acceptable salt thereof, wherein the subject has been previously administered an aromatase inhibitor.

[0219] In some aspects, the present disclosure provides methods of treating a PTEN deficient cancer comprising, administering to a subject in need thereof an AKT1 selective inhibitor, wherein the subject has been previously administered a CDK2 inhibitor. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound B or a pharmaceutically acceptable salt thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound C or a pharmaceutically acceptable salt thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound D or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure providesWSGR Docket No. 61402-725.601methods of treating a PTEN deficient cancer comprising, administering to the subject in need thereof Compound A or a pharmaceutically acceptable salt thereof, wherein the subject has been previously administered a CDK2 inhibitor.

[0220] In some aspects, the present disclosure provides methods of treating a PTEN deficient cancer comprising, administering to a subject in need thereof an AKT1 selective inhibitor, wherein the subject has been previously administered a CDK4 / 6 inhibitor. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound B or a pharmaceutically acceptable salt thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound C or a pharmaceutically acceptable salt thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound D or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides methods of treating a PTEN deficient cancer comprising, administering to the subject in need thereof Compound A or a pharmaceutically acceptable salt thereof, wherein the subject has been previously administered a CDK4 / 6 inhibitor.

[0221] In some aspects, the present disclosure provides methods of treating a PTEN deficient cancer comprising, administering to a subject in need thereof an AKT1 selective inhibitor, wherein the subject has been previously administered an anti-androgen. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound B or a pharmaceutically acceptable salt thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound C or a pharmaceutically acceptable salt thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound D or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides methods of treating a PTEN deficient cancer comprising, administering to the subject in need thereof Compound A or a pharmaceutically acceptable salt thereof, wherein the subject has been previously administered an anti-androgen.

[0222] In some aspects, the present disclosure provides methods of treating a PTEN deficient cancer comprising, administering to a subject in need thereof an AKT1 selective inhibitor,WSGR Docket No. 61402-725.601wherein the subject has been previously administered a selective estrogen receptor degrader (SERD) and a CDK4 / 6 inhibitor. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound B or a pharmaceutically acceptable salt thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound C or a pharmaceutically acceptable salt thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound D or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides methods of treating a PTEN deficient cancer comprising, administering to the subject in need thereof Compound A or a pharmaceutically acceptable salt thereof, wherein the subject has been previously administered a SERD and a CDK4 / 6 inhibitor.

[0223] In some aspects, the present disclosure provides methods of treating a PTEN deficient cancer comprising, administering to a subject in need thereof an AKT1 selective inhibitor, wherein the subject has been previously administered an aromatase inhibitor and a CDK4 / 6 inhibitor. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound B or a pharmaceutically acceptable salt thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound C or a pharmaceutically acceptable salt thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound D or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides methods of treating a PTEN deficient cancer comprising, administering to the subject in need thereof Compound A or a pharmaceutically acceptable salt thereof, wherein the subject has been previously administered an aromatase inhibitor and a CDK4 / 6 inhibitor.

[0224] In some embodiments, the method of treating a PTEN deficient cancer comprises, administering to a subject in need thereof an AKT1 selective inhibitor and a second agent selected from a CDK2 inhibitor, a CDK4 / 6 inhibitor, an aromatase inhibitor, an anti -androgen, an androgen synthesis inhibitor, an mTOR inhibitor, a PI3Ka inhibitor, a PI3Ka mutant inhibitor, a gonadotropin-releasing hormone (GnRH) agonist, a selective estrogen receptorWSGR Docket No. 61402-725.601modulator (SERM), and a selective estrogen receptor degrader (SERD). In some embodiments, the subject is a second agent selected from a CDK2 inhibitor, a CDK4 / 6 inhibitor, an aromatase inhibitor, an anti-androgen, an androgen synthesis inhibitor, an mTOR inhibitor, a PI3Ka inhibitor, a PI3Ka mutant inhibitor, a gonadotropin-releasing hormone (GnRH) agonist, a selective estrogen receptor modulator (SERM), and a selective estrogen receptor degrader (SERD). In some embodiments, the second agent is a CDK2 inhibitor. In some embodiments, the second agent is a CDK4 / 6 inhibitor. In some embodiments, the second agent is an aromatase inhibitor. In some embodiments, the second agent is an anti-androgen. In some embodiments, the second agent is an androgen synthesis inhibitor. In some embodiments, the second agent is an mTOR inhibitor. the second agent is a PI3Kα inhibitor. In some embodiments, the second agent is a PI3Ka mutant inhibitor. In some embodiments, the second agent is a gonadotropin-releasing hormone (GnRH) agonist. In some embodiments, the second agent is a selective estrogen receptor modulator (SERM). In some embodiments, the second agent is a selective estrogen receptor degrader (SERD).

[0225] In some embodiments, the method of treating a PTEN deficient cancer comprises, administering to a subject in need thereof Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof and a second agent selected from a CDK2 inhibitor, a CDK4 / 6 inhibitor, an aromatase inhibitor, an anti-androgen, an androgen synthesis inhibitor, an mTOR inhibitor, a PI3Ka inhibitor, a PI3Ka mutant inhibitor, a gonadotropin-releasing hormone (GnRH) agonist, a selective estrogen receptor modulator (SERM), and a selective estrogen receptor degrader (SERD). In some embodiments, the method of treating a PTEN deficient cancer comprises, administering to a subject in need thereof Compound A or pharmaceutically acceptable salt thereof and a second agent selected from a CDK2 inhibitor, a CDK4 / 6 inhibitor, an aromatase inhibitor, an anti-androgen, an androgen synthesis inhibitor, an mTOR inhibitor, a PI3Ka inhibitor, a PI3Ka mutant inhibitor, a gonadotropin-releasing hormone (GnRH) agonist, a selective estrogen receptor modulator (SERM), and a selective estrogen receptor degrader (SERD). In some embodiments, the subject is a second agent selected from a CDK2 inhibitor, a CDK4 / 6 inhibitor, an aromatase inhibitor, an anti -androgen, an androgen synthesis inhibitor, an mTOR inhibitor, a PI3Ka inhibitor, a PI3Ka mutant inhibitor, a gonadotropin-releasing hormone (GnRH) agonist, a selective estrogen receptor modulator (SERM), and a selective estrogen receptor degrader (SERD). In some embodiments, the second agent is a CDK2 inhibitor. In some embodiments, the second agent is a CDK4 / 6 inhibitor. In some embodiments, the second agent is an aromatase inhibitor. In some embodiments, the second agent is an antiandrogen. In some embodiments, the second agent is an androgen synthesis inhibitor. In some embodiments, the second agent is an mTOR inhibitor, the second agent is a PI3Ka inhibitor. InWSGR Docket No. 61402-725.601some embodiments, the second agent is a PI3Ka mutant inhibitor. In some embodiments, the second agent is a gonadotropin-releasing hormone (GnRH) agonist. In some embodiments, the second agent is a selective estrogen receptor modulator (SERM). In some embodiments, the second agent is a selective estrogen receptor degrader (SERD).

[0226] In some aspects, the present disclosure provides methods of treating a PTEN deficient cancer comprising, administering to the subject in need thereof Compound A, B, C, or D, or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides methods of treating cancer comprising identifying a subject with a PTEN deficient cancer; and administering to the subject in need thereof Compound A, B, C, or D, or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides methods of treating cancer comprising selecting a subject with a PTEN deficient cancer; and administering to the subject in need thereof Compound A, B, C, or D, or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides methods of treating cancer comprising screening to identify a subject with a PTEN deficient cancer; and administering to the subject in need thereof Compound A, B, C, or D, or a pharmaceutically acceptable salt thereof.

[0227] In some aspects, the present disclosure provides methods of treating a PTEN deficient cancer comprising, administering to the subject in need thereof Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides methods of treating cancer comprising identifying a subject with a PTEN deficient cancer; and administering to the subject in need thereof Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides methods of treating cancer comprising selecting a subject with a PTEN deficient cancer; and administering to the subject in need thereof Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides methods of treating cancer comprising screening to identify a subject with a PTEN deficient cancer; and administering to the subject in need thereof Compound A or a pharmaceutically acceptable salt thereof.

[0228] In some embodiments, the subject has a relapsed or refractory cancer after receiving at least one prior treatment. In some embodiments, the subject has a relapsed cancer after receiving at least one prior treatment. In some embodiments, the subject has a refractory cancer after receiving at least one prior treatment. In some embodiments, the at least one prior treatment comprises from a CDK2 inhibitor, a CDK4 / 6 inhibitor, an aromatase inhibitor, an anti-androgen, an androgen synthesis inhibitor, an mTOR inhibitor, a PI3Kα inhibitor, a PI3Kα mutant inhibitor, a gonadotropin-releasing hormone (GnRH) agonist, a selective estrogen receptor modulator (SERM), a selective estrogen receptor degrader (SERD), or a combination thereof. InWSGR Docket No. 61402-725.601some embodiments, the at least one prior treatment is selected from surgery, radiation, chemotherapy, and a combination thereof. In some embodiments, the at least one prior treatment is selected from surgery, radiation, and chemotherapy.

[0229] In some embodiments, the at least one prior treatment is radiation.

[0230] In some embodiments, the at least one prior treatment is chemotherapy. In some embodiments, the chemotherapy is selected from a CDK2 inhibitor, a CDK4 / 6 inhibitor, an aromatase inhibitor, an anti-androgen, an androgen synthesis inhibitor, an mTOR inhibitor, a PI3Kα inhibitor, a PI3Kα mutant inhibitor, a gonadotropin-releasing hormone (GnRH) agonist, a selective estrogen receptor modulator (SERM), a selective estrogen receptor degrader (SERD, and a combination thereof. In some embodiments, the chemotherapy is selected from a CDK2 inhibitor, a CDK4 / 6 inhibitor, an aromatase inhibitor, an anti -androgen, and a selective estrogen receptor degrader (SERD). In some embodiments, the chemotherapy is a CDK2 inhibitor. In some embodiments, the chemotherapy is a CDK4 / 6 inhibitor. In some embodiments, the chemotherapy is an aromatase inhibitor. In some embodiments, the chemotherapy is an antiandrogen. In some embodiments, the chemotherapy is a selective estrogen receptor degrader (SERD).

[0231] In some embodiments, the at least one prior treatment is surgery. In some embodiments, the surgery is a complete resection or a partial resection. In some embodiments, the surgery is a complete resection. In some embodiments, the surgery is a partial resection.

[0232] In some embodiments, the PTEN deficient cancer is a solid tumor. In some embodiments, the PTEN deficient cancer is selected from breast cancer, kidney cancer, prostate cancer, head and neck cancer, gastric cancer, lung cancer, endometrial cancer, ovarian cancer, cervical cancer, esophageal cancer, and colon cancer. In some embodiments, the PTEN deficient cancer is breast cancer. In some embodiments, the breast cancer is ER+ / HER2- breast cancer. In some embodiments, the breast cancer is triple negative breast cancer. In some embodiments, the PTEN deficient cancer is kidney cancer. In some embodiments, the kidney cancer is renal cell carcinoma. In some embodiments, the PTEN deficient cancer is prostate cancer. In some embodiments, the prostate cancer is castration resistant prostate cancer. In some embodiments, the PTEN deficient cancer is head and neck cancer. In some embodiments, the head and neck cancer is head and neck squamous cell carcinoma. In some embodiments, the PTEN deficient cancer is gastric cancer. In some embodiments, the PTEN deficient cancer is lung cancer. In some embodiments, the lung cancer is squamous cell lung cancer. In some embodiments, the PTEN deficient cancer is endometrial cancer. In some embodiments, the PTEN deficient cancer is colon cancer. In some embodiments, the colon cancer is colorectal cancer. In some embodiments, the PTEN deficient cancer is ovarian cancer. In some embodiments, the PTENWSGR Docket No. 61402-725.601deficient cancer is cervical cancer. In some embodiments, the PTEN deficient cancer is esophageal cancer. In some embodiments, the esophageal cancer is squamous cell esophageal cancer.

[0233] Methods of treating a PTEN altered cancer

[0234] In some aspects, the present disclosure provides methods of treating a PTEN altered cancer comprising, administering to a subject in need thereof an AKT1 selective inhibitor. In some embodiments, the method of treating a PTEN altered cancer comprising, administering to a subject in need thereof an AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the method comprises identifying a subject with a PTEN altered cancer. In some embodiments, the method comprises selecting a subject with a PTEN altered cancer. In some embodiments, the method comprises screening to identify a subject with a PTEN altered cancer.

[0235] In some aspects, the present disclosure provides methods of treating cancer comprising identifying a subject with a PTEN altered cancer; and administering to the subject an AKT1 selective inhibitor. In some embodiments, the present disclosure provides methods of treating cancer comprising identifying a subject with a PTEN altered cancer; and administering to the subject an AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A or a pharmaceutically acceptable salt thereof.

[0236] In some aspects, the present disclosure provides methods of treating cancer comprising selecting a subject with a PTEN altered cancer; and administering to the subject an AKT1 selective inhibitor. In some embodiments, the present disclosure provides methods of treating cancer comprising selecting a subject with a PTEN altered cancer; and administering to the subject an AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A or a pharmaceutically acceptable salt thereof.

[0237] In some aspects, the present disclosure provides methods of treating cancer comprising screening to identify a subject with a PTEN altered cancer; and administering to the subjectWSGR Docket No. 61402-725.601identified in the screen an AKT1 selective inhibitor. In some embodiments, the present disclosure provides methods of treating cancer comprising screening to identify a subject with a PTEN altered cancer; and administering to the subject identified in the screen an AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A or a pharmaceutically acceptable salt thereof.

[0238] In some aspects, the present disclosure provides methods of treating a PTEN altered cancer comprising, administering to a subject in need thereof an AKT1 selective inhibitor, wherein the subject has a relapsed or refractory cancer after receiving at least one prior treatment. In some embodiments, the method of treating a PTEN altered cancer comprises, administering to a subject in need thereof an AKT1 selective inhibitor, wherein the subject has a relapsed cancer after receiving at least one prior treatment. In some embodiments, the method of treating a PTEN altered cancer comprises, administering to a subject in need thereof an AKT1 selective inhibitor, wherein the subject has a refractory cancer after receiving at least one prior treatment.

[0239] In some aspects, the present disclosure provides methods of treating a PTEN altered cancer comprising, administering to a subject in need thereof Compound A, B, C, or D, or a pharmaceutically acceptable salt thereof, wherein the subject has a relapsed or refractory cancer after receiving at least one prior treatment. In some embodiments, the method of treating a PTEN altered cancer comprises, administering to a subject in need thereof Compound A, B, C, or D, or a pharmaceutically acceptable salt thereof, wherein the subject has a relapsed cancer after receiving at least one prior treatment. In some embodiments, the method of treating a PTEN altered cancer comprises, administering to a subject in need thereof Compound A, B, C, or D, or a pharmaceutically acceptable salt thereof, wherein the subject has a refractory cancer after receiving at least one prior treatment.

[0240] In some aspects, the present disclosure provides methods of treating a PTEN altered cancer comprising, administering to a subject in need thereof Compound A or a pharmaceutically acceptable salt thereof, wherein the subject has a relapsed or refractory cancer after receiving at least one prior treatment. In some embodiments, the method of treating a PTEN altered cancer comprises, administering to a subject in need thereof Compound A or a pharmaceutically acceptable salt thereof, wherein the subject has a relapsed cancer after receiving at least one prior treatment. In some embodiments, the method of treating a PTEN altered cancer comprises, administering to a subject in need thereof Compound A or aWSGR Docket No. 61402-725.601pharmaceutically acceptable salt thereof, wherein the subject has a refractory cancer after receiving at least one prior treatment.

[0241] In some embodiments, the at least one prior treatment comprises a selective estrogen receptor degrader (SERD), an aromatase inhibitor, a CDK4 / 6 inhibitor, an anti-androgen, or a combination thereof. In some embodiments, the subject has been previously administered a selective estrogen receptor degrader (SERD), an aromatase inhibitor, a CDK4 / 6 inhibitor, an anti-androgen, or a combination thereof. In some embodiments, the at least one prior treatment is a standard of care treatment. In some embodiments, the standard of care treatment is a recognized standard for cancer treatment under the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology.

[0242] In some aspects, the present disclosure provides methods of treating a PTEN altered cancer comprising, administering to a subject in need thereof an AKT1 selective inhibitor, wherein the subject has been previously administered a selective estrogen receptor degrader (SERD). In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides methods of treating a PTEN altered cancer comprising, administering to the subject in need thereof Compound A or a pharmaceutically acceptable salt thereof, wherein the subject has been previously administered a SERD.

[0243] In some aspects, the present disclosure provides methods of treating a PTEN altered cancer comprising, administering to a subject in need thereof an AKT1 selective inhibitor, wherein the subject has been previously administered an aromatase inhibitor. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides methods of treating a PTEN altered cancer comprising, administering to the subject in need thereof Compound A or a pharmaceutically acceptable salt thereof, wherein the subject has been previously administered an aromatase inhibitor.

[0244] In some aspects, the present disclosure provides methods of treating a PTEN altered cancer comprising, administering to a subject in need thereof an AKT1 selective inhibitor, wherein the subject has been previously administered a CDK2 inhibitor. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof. In some embodiments, the AKT1WSGR Docket No. 61402-725.601selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides methods of treating a PTEN altered cancer comprising, administering to the subject in need thereof Compound A or a pharmaceutically acceptable salt thereof, wherein the subject has been previously administered a CDK2 inhibitor.

[0245] In some aspects, the present disclosure provides methods of treating a PTEN altered cancer comprising, administering to a subject in need thereof an AKT1 selective inhibitor, wherein the subject has been previously administered a CDK4 / 6 inhibitor. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides methods of treating a PTEN altered cancer comprising, administering to the subject in need thereof Compound A or a pharmaceutically acceptable salt thereof, wherein the subject has been previously administered a CDK4 / 6 inhibitor.

[0246] In some aspects, the present disclosure provides methods of treating a PTEN altered cancer comprising, administering to a subject in need thereof an AKT1 selective inhibitor, wherein the subject has been previously administered an anti-androgen. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides methods of treating a PTEN altered cancer comprising, administering to the subject in need thereof Compound A or a pharmaceutically acceptable salt thereof, wherein the subject has been previously administered an anti-androgen.

[0247] In some aspects, the present disclosure provides methods of treating a PTEN altered cancer comprising, administering to a subject in need thereof an AKT1 selective inhibitor, wherein the subject has been previously administered a selective estrogen receptor degrader (SERD) and a CDK4 / 6 inhibitor. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides methods of treating a PTEN altered cancer comprising, administering to the subject in need thereof Compound A or aWSGR Docket No. 61402-725.601pharmaceutically acceptable salt thereof, wherein the subject has been previously administered a SERD and a CDK4 / 6 inhibitor.

[0248] In some aspects, the present disclosure provides methods of treating a PTEN altered cancer comprising, administering to a subject in need thereof an AKT1 selective inhibitor, wherein the subject has been previously administered an aromatase inhibitor and a CDK4 / 6 inhibitor. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides methods of treating a PTEN altered cancer comprising, administering to the subject in need thereof Compound A or a pharmaceutically acceptable salt thereof, wherein the subject has been previously administered an aromatase inhibitor and a CDK4 / 6 inhibitor.

[0249] In some embodiments, the method of treating a PTEN altered cancer comprises, administering to a subject in need thereof an AKT1 selective inhibitor and a second agent selected from a CDK2 inhibitor, a CDK4 / 6 inhibitor, an aromatase inhibitor, an anti -androgen, an androgen synthesis inhibitor, an mTOR inhibitor, a PI3Ka inhibitor, a PI3Ka mutant inhibitor, a gonadotropin-releasing hormone (GnRH) agonist, a selective estrogen receptor modulator (SERM), and a selective estrogen receptor degrader (SERD). In some embodiments, the subject is a second agent selected from a CDK2 inhibitor, a CDK4 / 6 inhibitor, an aromatase inhibitor, an anti-androgen, an androgen synthesis inhibitor, an mTOR inhibitor, a PI3Ka inhibitor, a PI3Ka mutant inhibitor, a gonadotropin-releasing hormone (GnRH) agonist, a selective estrogen receptor modulator (SERM), and a selective estrogen receptor degrader (SERD). In some embodiments, the second agent is a CDK2 inhibitor. In some embodiments, the second agent is a CDK4 / 6 inhibitor. In some embodiments, the second agent is an aromatase inhibitor. In some embodiments, the second agent is an anti-androgen. In some embodiments, the second agent is an androgen synthesis inhibitor. In some embodiments, the second agent is an mTOR inhibitor. the second agent is a PI3Kα inhibitor. In some embodiments, the second agent is a PI3Ka mutant inhibitor. In some embodiments, the second agent is a gonadotropin-releasing hormone (GnRH) agonist. In some embodiments, the second agent is a selective estrogen receptor modulator (SERM). In some embodiments, the second agent is a selective estrogen receptor degrader (SERD).

[0250] In some embodiments, the method of treating a PTEN altered cancer comprises, administering to a subject in need thereof Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof and a second agent selected from a CDK2 inhibitor, a CDK4 / 6WSGR Docket No. 61402-725.601inhibitor, an aromatase inhibitor, an anti-androgen, an androgen synthesis inhibitor, an mTOR inhibitor, a PI3Kα inhibitor, a PI3Kα mutant inhibitor, a gonadotropin-releasing hormone (GnRH) agonist, a selective estrogen receptor modulator (SERM), and a selective estrogen receptor degrader (SERD). In some embodiments, the method of treating a PTEN altered cancer comprises, administering to a subject in need thereof Compound A or pharmaceutically acceptable salt thereof and a second agent selected from a CDK2 inhibitor, a CDK4 / 6 inhibitor, an aromatase inhibitor, an anti-androgen, an androgen synthesis inhibitor, an mTOR inhibitor, a PI3Kα inhibitor, a PI3Kα mutant inhibitor, a gonadotropin-releasing hormone (GnRH) agonist, a selective estrogen receptor modulator (SERM), and a selective estrogen receptor degrader (SERD). In some embodiments, the subject is a second agent selected from a CDK2 inhibitor, a CDK4 / 6 inhibitor, an aromatase inhibitor, an anti-androgen, an androgen synthesis inhibitor, an mTOR inhibitor, a PI3Kα inhibitor, a PI3Kα mutant inhibitor, a gonadotropin-releasing hormone (GnRH) agonist, a selective estrogen receptor modulator (SERM), and a selective estrogen receptor degrader (SERD). In some embodiments, the second agent is a CDK2 inhibitor. In some embodiments, the second agent is a CDK4 / 6 inhibitor. In some embodiments, the second agent is an aromatase inhibitor. In some embodiments, the second agent is an antiandrogen. In some embodiments, the second agent is an androgen synthesis inhibitor. In some embodiments, the second agent is an mTOR inhibitor, the second agent is a PI3Kα inhibitor. In some embodiments, the second agent is a PI3Ka mutant inhibitor. In some embodiments, the second agent is a gonadotropin-releasing hormone (GnRH) agonist. In some embodiments, the second agent is a selective estrogen receptor modulator (SERM). In some embodiments, the second agent is a selective estrogen receptor degrader (SERD).

[0251] In some aspects, the present disclosure provides methods of treating a PTEN altered cancer comprising, administering to the subject in need thereof Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof. In some embodiments, the present disclosure provides methods of treating cancer comprising: identifying a subject with a PTEN altered cancer; and administering to the subject in need thereof Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof. In some embodiments, the present disclosure provides methods of treating cancer comprising: selecting a subject with a PTEN altered cancer; and administering to the subject in need thereof Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof. In some embodiments, the present disclosure provides methods of treating cancer comprising: screening to identify a subject with a PTEN altered cancer; and administering to the subject in need thereof Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof.WSGR Docket No. 61402-725.601

[0252] In some aspects, the present disclosure provides methods of treating a PTEN altered cancer comprising, administering to the subject in need thereof Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides methods of treating cancer comprising: identifying a subject with a PTEN altered cancer; and administering to the subject in need thereof Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides methods of treating cancer comprising: selecting a subject with a PTEN altered cancer; and administering to the subject in need thereof Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides methods of treating cancer comprising: screening to identify a subject with a PTEN altered cancer; and administering to the subject in need thereof Compound A or a pharmaceutically acceptable salt thereof.

[0253] In some embodiments, the subject has a relapsed or refractory cancer after receiving at least one prior treatment. In some embodiments, the subject has a relapsed cancer after receiving at least one prior treatment. In some embodiments, the subject has a refractory cancer after receiving at least one prior treatment. In some embodiments, the at least one prior treatment comprises from a CDK2 inhibitor, a CDK4 / 6 inhibitor, an aromatase inhibitor, an anti-androgen, an androgen synthesis inhibitor, an mTOR inhibitor, a PI3Kα inhibitor, a PI3Kα mutant inhibitor, a gonadotropin-releasing hormone (GnRH) agonist, a selective estrogen receptor modulator (SERM), a selective estrogen receptor degrader (SERD), or a combination thereof. In some embodiments, the at least one prior treatment is selected from surgery, radiation, chemotherapy, and a combination thereof. In some embodiments, the at least one prior treatment is selected from surgery, radiation, and chemotherapy.

[0254] In some embodiments, the at least one prior treatment is radiation.

[0255] In some embodiments, the at least one prior treatment is chemotherapy. In some embodiments, the chemotherapy is selected from a CDK2 inhibitor, a CDK4 / 6 inhibitor, an aromatase inhibitor, an anti-androgen, an androgen synthesis inhibitor, an mTOR inhibitor, a PI3Kα inhibitor, a PI3Kα mutant inhibitor, a gonadotropin-releasing hormone (GnRH) agonist, a selective estrogen receptor modulator (SERM), a selective estrogen receptor degrader (SERD, and a combination thereof. In some embodiments, the chemotherapy is selected from a CDK2 inhibitor, a CDK4 / 6 inhibitor, an aromatase inhibitor, an anti -androgen, and a selective estrogen receptor degrader (SERD). In some embodiments, the chemotherapy is a CDK2 inhibitor. In some embodiments, the chemotherapy is a CDK4 / 6 inhibitor. In some embodiments, the chemotherapy is an aromatase inhibitor. In some embodiments, the chemotherapy is an antiandrogen. In some embodiments, the chemotherapy is a selective estrogen receptor degrader (SERD).WSGR Docket No. 61402-725.601

[0256] In some embodiments, the at least one prior treatment is surgery. In some embodiments, the surgery is a complete resection or a partial resection. In some embodiments, the surgery is a complete resection. In some embodiments, the surgery is a partial resection.

[0257] In some embodiments, the PTEN altered cancer is a solid tumor. In some embodiments, the PTEN altered cancer is selected from breast cancer, kidney cancer, prostate cancer, head and neck cancer, gastric cancer, lung cancer, endometrial cancer, ovarian cancer, cervical cancer, esophageal cancer, and colon cancer. In some embodiments, the PTEN altered cancer is breast cancer. In some embodiments, the breast cancer is ER+ / HER2- breast cancer. In some embodiments, the breast cancer is triple negative breast cancer. In some embodiments, the PTEN altered cancer is kidney cancer. In some embodiments, the kidney cancer is renal cell carcinoma. In some embodiments, the PTEN altered cancer is prostate cancer. In some embodiments, the prostate cancer is castration resistant prostate cancer. In some embodiments, the PTEN altered cancer is head and neck cancer. In some embodiments, the head and neck cancer is head and neck squamous cell carcinoma. In some embodiments, the PTEN altered cancer is gastric cancer. In some embodiments, the PTEN altered cancer is lung cancer. In some embodiments, the lung cancer is squamous cell lung cancer. In some embodiments, the PTEN altered cancer is endometrial cancer. In some embodiments, the PTEN altered cancer is colon cancer. In some embodiments, the colon cancer is colorectal cancer. In some embodiments, the PTEN altered cancer is ovarian cancer. In some embodiments, the PTEN altered cancer is cervical cancer. In some embodiments, the PTEN altered cancer is esophageal cancer. In some embodiments, the esophageal cancer is squamous cell esophageal cancer.

[0258] Methods of treating a PTEN mutated cancer

[0259] In some aspects, the present disclosure provides methods of treating a PTEN mutated cancer comprising, administering to a subject in need thereof an AKT1 selective inhibitor. In some embodiments, the method of treating a PTEN mutated cancer comprises, administering to a subject in need thereof an AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the method comprises identifying a subject with a PTEN mutated cancer. In some embodiments, the method comprises selecting a subject with a PTEN mutated cancer. In some embodiments, the method comprises screening to identify a subject with a PTEN mutated cancer.

[0260] In some aspects, the present disclosure provides methods of treating cancer comprising identifying a subject with a PTEN mutated cancer; and administering to the subject an AKT1WSGR Docket No. 61402-725.601selective inhibitor. In some embodiments, the present disclosure provides methods of treating cancer comprising identifying a subject with a PTEN mutated cancer; and administering to the subject an AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A or a pharmaceutically acceptable salt thereof.

[0261] In some aspects, the present disclosure provides methods of treating cancer comprising selecting a subject with a PTEN mutated cancer; and administering to the subject an AKT1 selective inhibitor. In some embodiments, the present disclosure provides methods of treating cancer comprising selecting a subject with a PTEN mutated cancer; and administering to the subject an AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A or a pharmaceutically acceptable salt thereof.

[0262] In some aspects, the present disclosure provides methods of treating cancer comprising screening to identify a subject with a PTEN mutated cancer; and administering to the subject identified in the screen an AKT1 selective inhibitor. In some embodiments, the present disclosure provides methods of treating cancer comprising screening to identify a subject with a PTEN mutated cancer; and administering to the subject identified in the screen an AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A or a pharmaceutically acceptable salt thereof.

[0263] In some aspects, the present disclosure provides methods of treating a PTEN mutated cancer comprising, administering to a subject in need thereof an AKT1 selective inhibitor, wherein the subject has a relapsed or refractory cancer after receiving at least one prior treatment. In some embodiments, the method of treating a PTEN mutated cancer comprises, administering to a subject in need thereof an AKT1 selective inhibitor, wherein the subject has a relapsed cancer after receiving at least one prior treatment. In some embodiments, the method of treating a PTEN mutated cancer comprises, administering to a subject in need thereof an AKT1 selective inhibitor, wherein the subject has a refractory cancer after receiving at least one prior treatment.WSGR Docket No. 61402-725.601

[0264] In some aspects, the present disclosure provides methods of treating a PTEN mutated cancer comprising, administering to a subject in need thereof Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof, wherein the subject has a relapsed or refractory cancer after receiving at least one prior treatment. In some embodiments, the method of treating a PTEN mutated cancer comprises, administering to a subject in need thereof Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof, wherein the subject has a relapsed cancer after receiving at least one prior treatment. In some embodiments, the method of treating a PTEN mutated cancer comprises, administering to a subject in need thereof Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof, wherein the subject has a refractory cancer after receiving at least one prior treatment.

[0265] In some aspects, the present disclosure provides methods of treating a PTEN mutated cancer comprising, administering to a subject in need thereof Compound A or a pharmaceutically acceptable salt thereof, wherein the subject has a relapsed or refractory cancer after receiving at least one prior treatment. In some embodiments, the method of treating a PTEN mutated cancer comprises, administering to a subject in need thereof Compound A or a pharmaceutically acceptable salt thereof, wherein the subject has a relapsed cancer after receiving at least one prior treatment. In some embodiments, the method of treating a PTEN mutated cancer comprises, administering to a subject in need thereof Compound A or a pharmaceutically acceptable salt thereof, wherein the subject has a refractory cancer after receiving at least one prior treatment.

[0266] In some embodiments, the at least one prior treatment comprises a selective estrogen receptor degrader (SERD), an aromatase inhibitor, a CDK4 / 6 inhibitor, an anti-androgen, or a combination thereof. In some embodiments, the subject has been previously administered a selective estrogen receptor degrader (SERD), an aromatase inhibitor, a CDK4 / 6 inhibitor, an anti-androgen, or a combination thereof. In some embodiments, the at least one prior treatment is a standard of care treatment. In some embodiments, the standard of care treatment is a recognized standard for cancer treatment under the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology.

[0267] In some aspects, the present disclosure provides methods of treating a PTEN mutated cancer comprising, administering to a subject in need thereof an AKT1 selective inhibitor, wherein the subject has been previously administered a selective estrogen receptor degrader (SERD). In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, theWSGR Docket No. 61402-725.601present disclosure provides methods of treating a PTEN mutated cancer comprising, administering to the subject in need thereof Compound A or a pharmaceutically acceptable salt thereof, wherein the subject has been previously administered a SERD.

[0268] In some aspects, the present disclosure provides methods of treating a PTEN mutated cancer comprising, administering to a subject in need thereof an AKT1 selective inhibitor, wherein the subject has been previously administered an aromatase inhibitor. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides methods of treating a PTEN mutated cancer comprising, administering to the subject in need thereof Compound A or a pharmaceutically acceptable salt thereof, wherein the subject has been previously administered an aromatase inhibitor.

[0269] In some aspects, the present disclosure provides methods of treating a PTEN mutated cancer comprising, administering to a subject in need thereof an AKT1 selective inhibitor, wherein the subject has been previously administered a CDK2 inhibitor. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides methods of treating a PTEN mutated cancer comprising, administering to the subject in need thereof Compound A or a pharmaceutically acceptable salt thereof, wherein the subject has been previously administered a CDK2 inhibitor.

[0270] In some aspects, the present disclosure provides methods of treating a PTEN mutated cancer comprising, administering to a subject in need thereof an AKT1 selective inhibitor, wherein the subject has been previously administered a CDK4 / 6 inhibitor. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides methods of treating a PTEN mutated cancer comprising, administering to the subject in need thereof Compound A or a pharmaceutically acceptable salt thereof, wherein the subject has been previously administered a CDK4 / 6 inhibitor.

[0271] In some aspects, the present disclosure provides methods of treating a PTEN mutated cancer comprising, administering to a subject in need thereof an AKT1 selective inhibitor,WSGR Docket No. 61402-725.601wherein the subject has been previously administered an anti-androgen. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides methods of treating a PTEN mutated cancer comprising, administering to the subject in need thereof Compound A or a pharmaceutically acceptable salt thereof, wherein the subject has been previously administered an anti-androgen.

[0272] In some aspects, the present disclosure provides methods of treating a PTEN mutated cancer comprising, administering to a subject in need thereof an AKT1 selective inhibitor, wherein the subject has been previously administered a selective estrogen receptor degrader (SERD) and a CDK4 / 6 inhibitor. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides methods of treating a PTEN mutated cancer comprising, administering to the subject in need thereof Compound A or a pharmaceutically acceptable salt thereof, wherein the subject has been previously administered a SERD and a CDK4 / 6 inhibitor.

[0273] In some aspects, the present disclosure provides methods of treating a PTEN mutated cancer comprising, administering to a subject in need thereof an AKT1 selective inhibitor, wherein the subject has been previously administered an aromatase inhibitor and a CDK4 / 6 inhibitor. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides methods of treating a PTEN mutated cancer comprising, administering to the subject in need thereof Compound A or a pharmaceutically acceptable salt thereof, wherein the subject has been previously administered an aromatase inhibitor and a CDK4 / 6 inhibitor.

[0274] In some embodiments, the method of treating a PTEN mutated cancer comprises, administering to a subject in need thereof an AKT1 selective inhibitor and a second agent selected from a CDK2 inhibitor, a CDK4 / 6 inhibitor, an aromatase inhibitor, an anti -androgen, an androgen synthesis inhibitor, an mTOR inhibitor, a PI3Ka inhibitor, a PI3Ka mutant inhibitor, a gonadotropin-releasing hormone (GnRH) agonist, a selective estrogen receptorWSGR Docket No. 61402-725.601modulator (SERM), and a selective estrogen receptor degrader (SERD). In some embodiments, the subject is a second agent selected from a CDK2 inhibitor, a CDK4 / 6 inhibitor, an aromatase inhibitor, an anti-androgen, an androgen synthesis inhibitor, an mTOR inhibitor, a PI3Ka inhibitor, a PI3Ka mutant inhibitor, a gonadotropin-releasing hormone (GnRH) agonist, a selective estrogen receptor modulator (SERM), and a selective estrogen receptor degrader (SERD). In some embodiments, the second agent is a CDK2 inhibitor. In some embodiments, the second agent is a CDK4 / 6 inhibitor. In some embodiments, the second agent is an aromatase inhibitor. In some embodiments, the second agent is an anti-androgen. In some embodiments, the second agent is an androgen synthesis inhibitor. In some embodiments, the second agent is an mTOR inhibitor. the second agent is a PI3Kα inhibitor. In some embodiments, the second agent is a PI3Ka mutant inhibitor. In some embodiments, the second agent is a gonadotropin-releasing hormone (GnRH) agonist. In some embodiments, the second agent is a selective estrogen receptor modulator (SERM). In some embodiments, the second agent is a selective estrogen receptor degrader (SERD).

[0275] In some embodiments, the method of treating a PTEN mutated cancer comprises, administering to a subject in need thereof Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof and a second agent selected from a CDK2 inhibitor, a CDK4 / 6 inhibitor, an aromatase inhibitor, an anti-androgen, an androgen synthesis inhibitor, an mTOR inhibitor, a PI3Kα inhibitor, a PI3Kα mutant inhibitor, a gonadotropin-releasing hormone (GnRH) agonist, a selective estrogen receptor modulator (SERM), and a selective estrogen receptor degrader (SERD). In some embodiments, the method of treating a PTEN mutated cancer comprises, administering to a subject in need thereof Compound A or pharmaceutically acceptable salt thereof and a second agent selected from a CDK2 inhibitor, a CDK4 / 6 inhibitor, an aromatase inhibitor, an anti-androgen, an androgen synthesis inhibitor, an mTOR inhibitor, a PI3Kα inhibitor, a PI3Kα mutant inhibitor, a gonadotropin-releasing hormone (GnRH) agonist, a selective estrogen receptor modulator (SERM), and a selective estrogen receptor degrader (SERD). In some embodiments, the subject is a second agent selected from a CDK2 inhibitor, a CDK4 / 6 inhibitor, an aromatase inhibitor, an anti-androgen, an androgen synthesis inhibitor, an mTOR inhibitor, a PI3Kα inhibitor, a PI3Kα mutant inhibitor, a gonadotropin-releasing hormone (GnRH) agonist, a selective estrogen receptor modulator (SERM), and a selective estrogen receptor degrader (SERD). In some embodiments, the second agent is a CDK2 inhibitor. In some embodiments, the second agent is a CDK4 / 6 inhibitor. In some embodiments, the second agent is an aromatase inhibitor. In some embodiments, the second agent is an antiandrogen. In some embodiments, the second agent is an androgen synthesis inhibitor. In some embodiments, the second agent is an mTOR inhibitor, the second agent is a PI3Kα inhibitor. InWSGR Docket No. 61402-725.601some embodiments, the second agent is a PI3Ka mutant inhibitor. In some embodiments, the second agent is a gonadotropin-releasing hormone (GnRH) agonist. In some embodiments, the second agent is a selective estrogen receptor modulator (SERM). In some embodiments, the second agent is a selective estrogen receptor degrader (SERD).

[0276] In some aspects, the present disclosure provides methods of treating a PTEN mutated cancer comprising, administering to a subject in need thereof administering to the subject in need thereof Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof. In some embodiments, the present disclosure provides methods of treating cancer comprising: identifying a subject with a PTEN mutated cancer; and administering to the subject in need thereof Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof. In some embodiments, the present disclosure provides methods of treating cancer comprising: selecting a subject with a PTEN mutated cancer; and administering to the subject in need thereof Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof. In some embodiments, the present disclosure provides methods of treating cancer comprising: screening to identify a subject with a PTEN mutated cancer; and administering to the subject in need thereof Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof.

[0277] In some aspects, the present disclosure provides methods of treating a PTEN mutated cancer comprising, administering to a subject in need thereof administering to the subject in need thereof Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides methods of treating cancer comprising: identifying a subject with a PTEN mutated cancer; and administering to the subject in need thereof Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides methods of treating cancer comprising: selecting a subject with a PTEN mutated cancer; and administering to the subject in need thereof Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides methods of treating cancer comprising: screening to identify a subject with a PTEN mutated cancer; and administering to the subject in need thereof Compound A or a pharmaceutically acceptable salt thereof.

[0278] In some embodiments, the subject has a relapsed or refractory cancer after receiving at least one prior treatment. In some embodiments, the subject has a relapsed cancer after receiving at least one prior treatment. In some embodiments, the subject has a refractory cancer after receiving at least one prior treatment. In some embodiments, the at least one prior treatment comprises from a CDK2 inhibitor, a CDK4 / 6 inhibitor, an aromatase inhibitor, an anti-androgen, an androgen synthesis inhibitor, an mTOR inhibitor, a PI3Kα inhibitor, a PI3Kα mutant inhibitor, a gonadotropin-releasing hormone (GnRH) agonist, a selective estrogen receptor modulator (SERM), a selective estrogen receptor degrader (SERD), or a combination thereof. InWSGR Docket No. 61402-725.601some embodiments, the at least one prior treatment is selected from surgery, radiation, chemotherapy, and a combination thereof. In some embodiments, the at least one prior treatment is selected from surgery, radiation, and chemotherapy.

[0279] In some embodiments, the at least one prior treatment is radiation.

[0280] In some embodiments, the at least one prior treatment is chemotherapy. In some embodiments, the chemotherapy is selected from a CDK2 inhibitor, a CDK4 / 6 inhibitor, an aromatase inhibitor, an anti-androgen, an androgen synthesis inhibitor, an mTOR inhibitor, a PI3Kα inhibitor, a PI3Kα mutant inhibitor, a gonadotropin-releasing hormone (GnRH) agonist, a selective estrogen receptor modulator (SERM), a selective estrogen receptor degrader (SERD, and a combination thereof. In some embodiments, the chemotherapy is selected from a CDK2 inhibitor, a CDK4 / 6 inhibitor, an aromatase inhibitor, an anti -androgen, and a selective estrogen receptor degrader (SERD). In some embodiments, the chemotherapy is a CDK2 inhibitor. In some embodiments, the chemotherapy is a CDK4 / 6 inhibitor. In some embodiments, the chemotherapy is an aromatase inhibitor. In some embodiments, the chemotherapy is an antiandrogen. In some embodiments, the chemotherapy is a selective estrogen receptor degrader (SERD).

[0281] In some embodiments, the at least one prior treatment is surgery. In some embodiments, the surgery is a complete resection or a partial resection. In some embodiments, the surgery is a complete resection. In some embodiments, the surgery is a partial resection.

[0282] In some embodiments, the PTEN mutated cancer is a solid tumor. In some embodiments, the PTEN mutated cancer is selected from breast cancer, kidney cancer, prostate cancer, head and neck cancer, gastric cancer, lung cancer, endometrial cancer, ovarian cancer, cervical cancer, esophageal cancer, and colon cancer. In some embodiments, the PTEN mutated cancer is breast cancer. In some embodiments, the breast cancer is ER+ / HER2- breast cancer. In some embodiments, the breast cancer is triple negative breast cancer. In some embodiments, the PTEN mutated cancer is kidney cancer. In some embodiments, the kidney cancer is renal cell carcinoma. In some embodiments, the PTEN mutated cancer is prostate cancer. In some embodiments, the prostate cancer is castration resistant prostate cancer. In some embodiments, the PTEN mutated cancer is head and neck cancer. In some embodiments, the head and neck cancer is head and neck squamous cell carcinoma. In some embodiments, the PTEN mutated cancer is gastric cancer. In some embodiments, the PTEN mutated cancer is lung cancer. In some embodiments, the lung cancer is squamous cell lung cancer. In some embodiments, the PTEN mutated cancer is endometrial cancer. In some embodiments, the PTEN mutated cancer is colon cancer. In some embodiments, the colon cancer is colorectal cancer. In some embodiments, the PTEN mutated cancer is ovarian cancer. In some embodiments, the PTENWSGR Docket No. 61402-725.601mutated cancer is cervical cancer. In some embodiments, the PTEN mutated cancer is esophageal cancer. In some embodiments, the esophageal cancer is squamous cell esophageal cancer.

[0283] Methods of treating a PIK3CA activated cancer

[0284] In some aspects, the present disclosure provides methods of treating a PIK3CA activated cancer comprising, administering to a subject in need thereof an AKT1 selective inhibitor. In some embodiments, the method of treating a PIK3CA activated cancer comprises, administering to a subject in need thereof an AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the method comprises identifying a subject with a PIK3CA activated cancer. In some embodiments, the method comprises selecting a subject with a PIK3CA activated cancer. In some embodiments, the method comprises screening to identify a subject with a PIK3CA activated cancer. In some embodiments, the PIK3CA activated cancer is a cancer comprising at least one mutation in an PIK3CA gene. In some embodiments, the AKT activated cancer is a cancer comprising at least one mutation in an PIK3CA protein.

[0285] In some aspects, the present disclosure provides methods of treating cancer comprising identifying a subject with a PIK3CA activated cancer; and administering to the subject an AKT1 selective inhibitor. In some embodiments, the present disclosure provides methods of treating cancer comprising identifying a subject with a PIK3CA activated cancer; and administering to the subject an AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A or a pharmaceutically acceptable salt thereof.

[0286] In some aspects, the present disclosure provides methods of treating cancer comprising selecting a subject with a PIK3CA activated cancer; and administering to the subject an AKT1 selective inhibitor. In some embodiments, the present disclosure provides methods of treating cancer comprising selecting a subject with a PIK3CA activated cancer; and administering to the subject an AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof. In someWSGR Docket No. 61402-725.601embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A or a pharmaceutically acceptable salt thereof.

[0287] In some aspects, the present disclosure provides methods of treating cancer comprising screening to identify a subject with a PIK3CA activated cancer; and administering to the subject identified in the screen an AKT1 selective inhibitor. In some embodiments, the present disclosure provides methods of treating cancer comprising screening to identify a subject with a PIK3CA activated cancer; and administering to the subject identified in the screen an AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A or a pharmaceutically acceptable salt thereof.

[0288] In some aspects, the present disclosure provides methods of treating a PIK3CA activated cancer comprising, administering to a subject in need thereof an AKT1 selective inhibitor, wherein the subject has a relapsed or refractory cancer after receiving at least one prior treatment. In some embodiments, the method of treating a PIK3CA activated cancer comprises, administering to a subject in need thereof an AKT1 selective inhibitor, wherein the subject has a relapsed cancer after receiving at least one prior treatment. In some embodiments, the method of treating a PIK3CA activated cancer comprises, administering to a subject in need thereof an AKT1 selective inhibitor, wherein the subject has a refractory cancer after receiving at least one prior treatment.

[0289] In some aspects, the present disclosure provides methods of treating a PIK3CA activated cancer comprising, administering to a subject in need thereof Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof, wherein the subject has a relapsed or refractory cancer after receiving at least one prior treatment. In some embodiments, the method of treating a PIK3CA activated cancer comprises, administering to a subject in need thereof Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof, wherein the subject has a relapsed cancer after receiving at least one prior treatment. In some embodiments, the method of treating a PIK3CA activated cancer comprises, administering to a subject in need thereof Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof, wherein the subject has a refractory cancer after receiving at least one prior treatment.

[0290] In some aspects, the present disclosure provides methods of treating a PIK3CA activated cancer comprising, administering to a subject in need thereof Compound A or a pharmaceutically acceptable salt thereof, wherein the subject has a relapsed or refractory cancer after receiving at least one prior treatment. In some embodiments, the method of treating aWSGR Docket No. 61402-725.601PIK3CA activated cancer comprises, administering to a subject in need thereof Compound A or a pharmaceutically acceptable salt thereof, wherein the subject has a relapsed cancer after receiving at least one prior treatment. In some embodiments, the method of treating a PIK3CA activated cancer comprises, administering to a subject in need thereof Compound A or a pharmaceutically acceptable salt thereof, wherein the subject has a refractory cancer after receiving at least one prior treatment.

[0291] In some embodiments, the at least one prior treatment comprises a selective estrogen receptor degrader (SERD), an aromatase inhibitor, a CDK4 / 6 inhibitor, an anti-androgen, or a combination thereof. In some embodiments, the subject has been previously administered a selective estrogen receptor degrader (SERD), an aromatase inhibitor, a CDK4 / 6 inhibitor, an anti-androgen, or a combination thereof. In some embodiments, the at least one prior treatment is a standard of care treatment. In some embodiments, the standard of care treatment is a recognized standard for cancer treatment under the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology.

[0292] In some aspects, the present disclosure provides methods of treating a PIK3CA activated cancer comprising, administering to a subject in need thereof an AKT1 selective inhibitor, wherein the subject has been previously administered a selective estrogen receptor degrader (SERD). In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides methods of treating a PIK3CA activated cancer comprising, administering to the subject in need thereof Compound A or a pharmaceutically acceptable salt thereof, wherein the subject has been previously administered a SERD.

[0293] In some aspects, the present disclosure provides methods of treating a PIK3CA activated cancer comprising, administering to a subject in need thereof an AKT1 selective inhibitor, wherein the subject has been previously administered an aromatase inhibitor. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides methods of treating a PIK3CA activated cancer comprising, administering to the subject in need thereof Compound A or a pharmaceutically acceptable salt thereof, wherein the subject has been previously administered an aromatase inhibitor.WSGR Docket No. 61402-725.601

[0294] In some aspects, the present disclosure provides methods of treating a PIK3CA activated cancer comprising, administering to a subject in need thereof an AKT1 selective inhibitor, wherein the subject has been previously administered a CDK2 inhibitor. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides methods of treating a PIK3CA activated cancer comprising, administering to the subject in need thereof Compound A or a pharmaceutically acceptable salt thereof, wherein the subject has been previously administered a CDK2 inhibitor.

[0295] In some aspects, the present disclosure provides methods of treating a PIK3CA activated cancer comprising, administering to a subject in need thereof an AKT1 selective inhibitor, wherein the subject has been previously administered a CDK4 / 6 inhibitor. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides methods of treating a PIK3CA activated cancer comprising, administering to the subject in need thereof Compound A or a pharmaceutically acceptable salt thereof, wherein the subject has been previously administered a CDK4 / 6 inhibitor.

[0296] In some aspects, the present disclosure provides methods of treating a PIK3CA activated cancer comprising, administering to a subject in need thereof an AKT1 selective inhibitor, wherein the subject has been previously administered an anti-androgen. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides methods of treating a PIK3CA activated cancer comprising, administering to the subject in need thereof Compound A or a pharmaceutically acceptable salt thereof, wherein the subject has been previously administered an anti-androgen.

[0297] In some aspects, the present disclosure provides methods of treating a PIK3CA activated cancer comprising, administering to a subject in need thereof an AKT1 selective inhibitor, wherein the subject has been previously administered a selective estrogen receptor degrader (SERD) and a CDK4 / 6 inhibitor. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A, B, C, or D, or a pharmaceuticallyWSGR Docket No. 61402-725.601acceptable salt of any one thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides methods of treating a PIK3CA activated cancer comprising, administering to the subject in need thereof Compound A or a pharmaceutically acceptable salt thereof, wherein the subject has been previously administered a SERD and a CDK4 / 6 inhibitor.

[0298] In some aspects, the present disclosure provides methods of treating a PIK3CA activated cancer comprising, administering to a subject in need thereof an AKT1 selective inhibitor, wherein the subject has been previously administered an aromatase inhibitor and a CDK4 / 6 inhibitor. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides methods of treating a PIK3CA activated cancer comprising, administering to the subject in need thereof Compound A or a pharmaceutically acceptable salt thereof, wherein the subject has been previously administered an aromatase inhibitor and a CDK4 / 6 inhibitor.

[0299] In some embodiments, the method of treating a PIK3CA activated cancer comprises, administering to a subject in need thereof an AKT1 selective inhibitor and a second agent selected from a CDK2 inhibitor, a CDK4 / 6 inhibitor, an aromatase inhibitor, an anti -androgen, an androgen synthesis inhibitor, an mTOR inhibitor, a PI3Ka inhibitor, a PI3Ka mutant inhibitor, a gonadotropin-releasing hormone (GnRH) agonist, a selective estrogen receptor modulator (SERM), and a selective estrogen receptor degrader (SERD). In some embodiments, the subject is a second agent selected from a CDK2 inhibitor, a CDK4 / 6 inhibitor, an aromatase inhibitor, an anti-androgen, an androgen synthesis inhibitor, an mTOR inhibitor, a PI3Ka inhibitor, a PI3Ka mutant inhibitor, a gonadotropin-releasing hormone (GnRH) agonist, a selective estrogen receptor modulator (SERM), and a selective estrogen receptor degrader (SERD). In some embodiments, the second agent is a CDK2 inhibitor. In some embodiments, the second agent is a CDK4 / 6 inhibitor. In some embodiments, the second agent is an aromatase inhibitor. In some embodiments, the second agent is an anti-androgen. In some embodiments, the second agent is an androgen synthesis inhibitor. In some embodiments, the second agent is an mTOR inhibitor. the second agent is a PI3Kα inhibitor. In some embodiments, the second agent is a PI3Ka mutant inhibitor. In some embodiments, the second agent is a gonadotropin-releasing hormone (GnRH) agonist. In some embodiments, the second agent is a selectiveWSGR Docket No. 61402-725.601estrogen receptor modulator (SERM). In some embodiments, the second agent is a selective estrogen receptor degrader (SERD).

[0300] In some embodiments, the method of treating a PIK3CA activated cancer comprises, administering to a subject in need thereof Compound A, B, C, or D, or pharmaceutically acceptable salt of any one thereof and a second agent selected from a CDK2 inhibitor, a CDK4 / 6 inhibitor, an aromatase inhibitor, an anti-androgen, an androgen synthesis inhibitor, an mTOR inhibitor, a PI3Ka inhibitor, a PI3Ka mutant inhibitor, a gonadotropin-releasing hormone (GnRH) agonist, a selective estrogen receptor modulator (SERM), and a selective estrogen receptor degrader (SERD). In some embodiments, the method of treating a PIK3CA activated cancer comprises, administering to a subject in need thereof Compound A or pharmaceutically acceptable salt thereof and a second agent selected from a CDK2 inhibitor, a CDK4 / 6 inhibitor, an aromatase inhibitor, an anti-androgen, an androgen synthesis inhibitor, an mTOR inhibitor, a PI3Kα inhibitor, a PI3Kα mutant inhibitor, a gonadotropin-releasing hormone (GnRH) agonist, a selective estrogen receptor modulator (SERM), and a selective estrogen receptor degrader (SERD). In some embodiments, the subject is a second agent selected from a CDK2 inhibitor, a CDK4 / 6 inhibitor, an aromatase inhibitor, an anti -androgen, an androgen synthesis inhibitor, an mTOR inhibitor, a PI3Kα inhibitor, a PI3Kα mutant inhibitor, a gonadotropin-releasing hormone (GnRH) agonist, a selective estrogen receptor modulator (SERM), and a selective estrogen receptor degrader (SERD). In some embodiments, the second agent is a CDK2 inhibitor. In some embodiments, the second agent is a CDK4 / 6 inhibitor. In some embodiments, the second agent is an aromatase inhibitor. In some embodiments, the second agent is an antiandrogen. In some embodiments, the second agent is an androgen synthesis inhibitor. In some embodiments, the second agent is an mTOR inhibitor, the second agent is a PI3Kα inhibitor. In some embodiments, the second agent is a PI3Kα mutant inhibitor. In some embodiments, the second agent is a gonadotropin-releasing hormone (GnRH) agonist. In some embodiments, the second agent is a selective estrogen receptor modulator (SERM). In some embodiments, the second agent is a selective estrogen receptor degrader (SERD).

[0301] In some aspects, the present disclosure provides methods of treating a PIK3CA activated cancer comprising, administering to a subject in need thereof administering to the subject in need thereof Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof. In some embodiments, the present disclosure provides methods of treating cancer comprising: identifying a subject with a PIK3CA activated cancer; and administering to the subject in need thereof Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof. In some embodiments, the present disclosure provides methods of treating cancer comprising: selecting a subject with a PIK3CA activated cancer; and administering to the subject in needWSGR Docket No. 61402-725.601thereof Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof. In some embodiments, the present disclosure provides methods of treating cancer comprising: screening to identify a subject with a PIK3CA activated cancer; and administering to the subject in need thereof Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof.

[0302] In some aspects, the present disclosure provides methods of treating a PIK3CA activated cancer comprising, administering to a subject in need thereof administering to the subject in need thereof Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides methods of treating cancer comprising: identifying a subject with a PIK3CA activated cancer; and administering to the subject in need thereof Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides methods of treating cancer comprising: selecting a subject with a PIK3CA activated cancer; and administering to the subject in need thereof Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides methods of treating cancer comprising: screening to identify a subject with a PIK3CA activated cancer; and administering to the subject in need thereof Compound A or a pharmaceutically acceptable salt thereof.

[0303] In some embodiments, the subject has a relapsed or refractory cancer after receiving at least one prior treatment. In some embodiments, the subject has a relapsed cancer after receiving at least one prior treatment. In some embodiments, the subject has a refractory cancer after receiving at least one prior treatment. In some embodiments, the at least one prior treatment comprises from a CDK2 inhibitor, a CDK4 / 6 inhibitor, an aromatase inhibitor, an anti-androgen, an androgen synthesis inhibitor, an mTOR inhibitor, a PI3Kα inhibitor, a PI3Kα mutant inhibitor, a gonadotropin-releasing hormone (GnRH) agonist, a selective estrogen receptor modulator (SERM), a selective estrogen receptor degrader (SERD), or a combination thereof. In some embodiments, the at least one prior treatment is selected from surgery, radiation, chemotherapy, and a combination thereof. In some embodiments, the at least one prior treatment is selected from surgery, radiation, and chemotherapy.

[0304] In some embodiments, the at least one prior treatment is radiation.

[0305] In some embodiments, the at least one prior treatment is chemotherapy. In some embodiments, the chemotherapy is selected from a CDK2 inhibitor, a CDK4 / 6 inhibitor, an aromatase inhibitor, an anti-androgen, an androgen synthesis inhibitor, an mTOR inhibitor, a PI3Kα inhibitor, a PI3Kα mutant inhibitor, a gonadotropin-releasing hormone (GnRH) agonist, a selective estrogen receptor modulator (SERM), a selective estrogen receptor degrader (SERD, and a combination thereof. In some embodiments, the chemotherapy is selected from a CDK2 inhibitor, a CDK4 / 6 inhibitor, an aromatase inhibitor, an anti -androgen, and a selective estrogenWSGR Docket No. 61402-725.601receptor degrader (SERD). In some embodiments, the chemotherapy is a CDK2 inhibitor. In some embodiments, the chemotherapy is a CDK4 / 6 inhibitor. In some embodiments, the chemotherapy is an aromatase inhibitor. In some embodiments, the chemotherapy is an antiandrogen. In some embodiments, the chemotherapy is a selective estrogen receptor degrader (SERD).

[0306] In some embodiments, the at least one prior treatment is surgery. In some embodiments, the surgery is a complete resection or a partial resection. In some embodiments, the surgery is a complete resection. In some embodiments, the surgery is a partial resection.

[0307] In some embodiments, the PIK3CA activated cancer is a solid tumor. In some embodiments, the PIK3CA activated cancer is selected from breast cancer, kidney cancer, prostate cancer, head and neck cancer, gastric cancer, lung cancer, endometrial cancer, ovarian cancer, cervical cancer, esophageal cancer, and colon cancer. In some embodiments, the PIK3CA activated cancer is breast cancer. In some embodiments, the breast cancer is ER+ / HER2- breast cancer. In some embodiments, the breast cancer is triple negative breast cancer. In some embodiments, the PIK3CA activated cancer is kidney cancer. In some embodiments, the kidney cancer is renal cell carcinoma. In some embodiments, the PIK3CA activated cancer is prostate cancer. In some embodiments, the prostate cancer is castration resistant prostate cancer. In some embodiments, the PIK3CA activated cancer is head and neck cancer. In some embodiments, the head and neck cancer is head and neck squamous cell carcinoma. In some embodiments, the PIK3CA activated cancer is gastric cancer. In some embodiments, the PIK3CA activated cancer is lung cancer. In some embodiments, the lung cancer is squamous cell lung cancer. In some embodiments, the PIK3CA activated cancer is endometrial cancer. In some embodiments, the PIK3CA activated cancer is colon cancer. In some embodiments, the colon cancer is colorectal cancer. In some embodiments, the PIK3CA activated cancer is ovarian cancer. In some embodiments, the PIK3CA activated cancer is cervical cancer. In some embodiments, the PIK3CA activated cancer is esophageal cancer. In some embodiments, the esophageal cancer is squamous cell esophageal cancer.

[0308] Methods of treating an AKT activated cancer

[0309] In some aspects, the present disclosure provides methods of treating an AKT activated cancer comprising, administering to a subject in need thereof an AKT1 selective inhibitor. In some embodiments, the method of treating an AKT activated cancer comprises, administering to a subject in need thereof an AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable saltWSGR Docket No. 61402-725.601thereof is Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the method comprises identifying a subject with an AKT activated cancer. In some embodiments, the method comprises selecting a subject with an AKT activated cancer. In some embodiments, the method comprises screening to identify a subject with an AKT activated cancer. In some embodiments, the AKT activated cancer is a cancer comprising at least one mutation in an AKT gene. In some embodiments, the AKT activated cancer is a cancer comprising at least one mutation in an AKT protein.

[0310] In some aspects, the present disclosure provides methods of treating cancer comprising identifying a subject with an AKT activated cancer; and administering to the subject an AKT1 selective inhibitor. In some embodiments, the present disclosure provides methods of treating cancer comprising identifying a subject with an AKT activated cancer; and administering to the subject an AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A or a pharmaceutically acceptable salt thereof.

[0311] In some aspects, the present disclosure provides methods of treating cancer comprising selecting a subject with an AKT activated cancer; and administering to the subject an AKT1 selective inhibitor. In some embodiments, the present disclosure provides methods of treating cancer comprising selecting a subject with an AKT activated cancer; and administering to the subject an AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A or a pharmaceutically acceptable salt thereof.

[0312] In some aspects, the present disclosure provides methods of treating cancer comprising screening to identify a subject with an AKT activated cancer; and administering to the subject identified in the screen an AKT1 selective inhibitor. In some embodiments, the present disclosure provides methods of treating cancer comprising screening to identify a subject with an AKT activated cancer; and administering to the subject identified in the screen an AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A or a pharmaceutically acceptable salt thereof.WSGR Docket No. 61402-725.601

[0313] In some aspects, the present disclosure provides methods of treating an AKT activated cancer comprising, administering to a subject in need thereof an AKT1 selective inhibitor, wherein the subject has a relapsed or refractory cancer after receiving at least one prior treatment. In some embodiments, the method of treating an AKT activated cancer comprises, administering to a subject in need thereof an AKT1 selective inhibitor, wherein the subject has a relapsed cancer after receiving at least one prior treatment. In some embodiments, the method of treating an AKT activated cancer comprises, administering to a subject in need thereof an AKT1 selective inhibitor, wherein the subject has a refractory cancer after receiving at least one prior treatment.

[0314] In some aspects, the present disclosure provides methods of treating an AKT activated cancer comprising, administering to a subject in need thereof Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof, wherein the subject has a relapsed or refractory cancer after receiving at least one prior treatment. In some embodiments, the method of treating an AKT activated cancer comprises, administering to a subject in need thereof Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof, wherein the subject has a relapsed cancer after receiving at least one prior treatment. In some embodiments, the method of treating an AKT activated cancer comprises, administering to a subject in need thereof Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof, wherein the subject has a refractory cancer after receiving at least one prior treatment.

[0315] In some aspects, the present disclosure provides methods of treating an AKT activated cancer comprising, administering to a subject in need thereof Compound A or a pharmaceutically acceptable salt thereof, wherein the subject has a relapsed or refractory cancer after receiving at least one prior treatment. In some embodiments, the method of treating an AKT activated cancer comprises, administering to a subject in need thereof Compound A or a pharmaceutically acceptable salt thereof, wherein the subject has a relapsed cancer after receiving at least one prior treatment. In some embodiments, the method of treating an AKT activated cancer comprises, administering to a subject in need thereof Compound A or a pharmaceutically acceptable salt thereof, wherein the subject has a refractory cancer after receiving at least one prior treatment.

[0316] In some embodiments, the at least one prior treatment comprises a selective estrogen receptor degrader (SERD), an aromatase inhibitor, a CDK4 / 6 inhibitor, an anti-androgen, or a combination thereof. In some embodiments, the subject has been previously administered a selective estrogen receptor degrader (SERD), an aromatase inhibitor, a CDK4 / 6 inhibitor, an anti-androgen, or a combination thereof. In some embodiments, the at least one prior treatment is a standard of care treatment. In some embodiments, the standard of care treatment is aWSGR Docket No. 61402-725.601recognized standard for cancer treatment under the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology.

[0317] In some aspects, the present disclosure provides methods of treating an AKT activated cancer comprising, administering to a subject in need thereof an AKT1 selective inhibitor, wherein the subject has been previously administered a selective estrogen receptor degrader (SERD). In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides methods of treating an AKT activated cancer comprising, administering to the subject in need thereof Compound A or a pharmaceutically acceptable salt thereof, wherein the subject has been previously administered a SERD.

[0318] In some aspects, the present disclosure provides methods of treating an AKT activated cancer comprising, administering to a subject in need thereof an AKT1 selective inhibitor, wherein the subject has been previously administered an aromatase inhibitor. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides methods of treating an AKT activated cancer comprising, administering to the subject in need thereof Compound A or a pharmaceutically acceptable salt thereof, wherein the subject has been previously administered an aromatase inhibitor.

[0319] In some aspects, the present disclosure provides methods of treating an AKT activated cancer comprising, administering to a subject in need thereof an AKT1 selective inhibitor, wherein the subject has been previously administered a CDK2 inhibitor. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides methods of treating an AKT activated cancer comprising, administering to the subject in need thereof Compound A or a pharmaceutically acceptable salt thereof, wherein the subject has been previously administered a CDK2 inhibitor.

[0320] In some aspects, the present disclosure provides methods of treating an AKT activated cancer comprising, administering to a subject in need thereof an AKT1 selective inhibitor, wherein the subject has been previously administered a CDK4 / 6 inhibitor. In someWSGR Docket No. 61402-725.601embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides methods of treating an AKT activated cancer comprising, administering to the subject in need thereof Compound A or a pharmaceutically acceptable salt thereof, wherein the subject has been previously administered a CDK4 / 6 inhibitor.

[0321] In some aspects, the present disclosure provides methods of treating an AKT activated cancer comprising, administering to a subject in need thereof an AKT1 selective inhibitor, wherein the subject has been previously administered an anti-androgen. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides methods of treating an AKT activated cancer comprising, administering to the subject in need thereof Compound A or a pharmaceutically acceptable salt thereof, wherein the subject has been previously administered an anti-androgen.

[0322] In some aspects, the present disclosure provides methods of treating an AKT activated cancer comprising, administering to a subject in need thereof an AKT1 selective inhibitor, wherein the subject has been previously administered a selective estrogen receptor degrader (SERD) and a CDK4 / 6 inhibitor. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides methods of treating an AKT activated cancer comprising, administering to the subject in need thereof Compound A or a pharmaceutically acceptable salt thereof, wherein the subject has been previously administered a SERD and a CDK4 / 6 inhibitor.

[0323] In some aspects, the present disclosure provides methods of treating an AKT activated cancer comprising, administering to a subject in need thereof an AKT1 selective inhibitor, wherein the subject has been previously administered an aromatase inhibitor and a CDK4 / 6 inhibitor. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof. In some embodiments, the AKT1 selective inhibitor or a pharmaceutically acceptable salt thereof is Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, theWSGR Docket No. 61402-725.601present disclosure provides methods of treating an AKT activated cancer comprising, administering to the subject in need thereof Compound A or a pharmaceutically acceptable salt thereof, wherein the subject has been previously administered an aromatase inhibitor and a CDK4 / 6 inhibitor.

[0324] In some embodiments, the method of treating an AKT activated cancer comprises, administering to a subject in need thereof an AKT1 selective inhibitor and a second agent selected from a CDK2 inhibitor, a CDK4 / 6 inhibitor, an aromatase inhibitor, an anti -androgen, an androgen synthesis inhibitor, an mTOR inhibitor, a PI3Ka inhibitor, a PI3Ka mutant inhibitor, a gonadotropin-releasing hormone (GnRH) agonist, a selective estrogen receptor modulator (SERM), and a selective estrogen receptor degrader (SERD). In some embodiments, the subject is a second agent selected from a CDK2 inhibitor, a CDK4 / 6 inhibitor, an aromatase inhibitor, an anti-androgen, an androgen synthesis inhibitor, an mTOR inhibitor, a PI3Ka inhibitor, a PI3Ka mutant inhibitor, a gonadotropin-releasing hormone (GnRH) agonist, a selective estrogen receptor modulator (SERM), and a selective estrogen receptor degrader (SERD). In some embodiments, the second agent is a CDK2 inhibitor. In some embodiments, the second agent is a CDK4 / 6 inhibitor. In some embodiments, the second agent is an aromatase inhibitor. In some embodiments, the second agent is an anti-androgen. In some embodiments, the second agent is an androgen synthesis inhibitor. In some embodiments, the second agent is an mTOR inhibitor. the second agent is a PI3Kα inhibitor. In some embodiments, the second agent is a PI3Ka mutant inhibitor. In some embodiments, the second agent is a gonadotropin-releasing hormone (GnRH) agonist. In some embodiments, the second agent is a selective estrogen receptor modulator (SERM). In some embodiments, the second agent is a selective estrogen receptor degrader (SERD).

[0325] In some embodiments, the method of treating an AKT activated cancer comprises, administering to a subject in need thereof Compound A, B, C, or D, or pharmaceutically acceptable salt of any one thereof and a second agent selected from a CDK2 inhibitor, a CDK4 / 6 inhibitor, an aromatase inhibitor, an anti-androgen, an androgen synthesis inhibitor, an mTOR inhibitor, a PI3Kα inhibitor, a PI3Kα mutant inhibitor, a gonadotropin-releasing hormone (GnRH) agonist, a selective estrogen receptor modulator (SERM), and a selective estrogen receptor degrader (SERD). In some embodiments, the method of treating an AKT activated cancer comprises, administering to a subject in need thereof Compound A or pharmaceutically acceptable salt thereof and a second agent selected from a CDK2 inhibitor, a CDK4 / 6 inhibitor, an aromatase inhibitor, an anti-androgen, an androgen synthesis inhibitor, an mTOR inhibitor, a PI3Kα inhibitor, a PI3Kα mutant inhibitor, a gonadotropin-releasing hormone (GnRH) agonist, a selective estrogen receptor modulator (SERM), and a selective estrogen receptor degraderWSGR Docket No. 61402-725.601(SERD). In some embodiments, the subject is a second agent selected from a CDK2 inhibitor, a CDK4 / 6 inhibitor, an aromatase inhibitor, an anti -androgen, an androgen synthesis inhibitor, an mTOR inhibitor, a PI3Ka inhibitor, a PI3Ka mutant inhibitor, a gonadotropin-releasing hormone (GnRH) agonist, a selective estrogen receptor modulator (SERM), and a selective estrogen receptor degrader (SERD). In some embodiments, the second agent is a CDK2 inhibitor. In some embodiments, the second agent is a CDK4 / 6 inhibitor. In some embodiments, the second agent is an aromatase inhibitor. In some embodiments, the second agent is an antiandrogen. In some embodiments, the second agent is an androgen synthesis inhibitor. In some embodiments, the second agent is an mTOR inhibitor, the second agent is a PI3Ka inhibitor. In some embodiments, the second agent is a PI3Ka mutant inhibitor. In some embodiments, the second agent is a gonadotropin-releasing hormone (GnRH) agonist. In some embodiments, the second agent is a selective estrogen receptor modulator (SERM). In some embodiments, the second agent is a selective estrogen receptor degrader (SERD).

[0326] In some aspects, the present disclosure provides methods of treating an AKT activated cancer comprising, administering to a subject in need thereof Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof. In some embodiments, the present disclosure provides methods of treating cancer comprising: identifying a subject with an AKT activated cancer; and administering to the subject in need thereof Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof. In some embodiments, the present disclosure provides methods of treating cancer comprising: selecting a subject with an AKT activated cancer; and administering to the subject in need thereof Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof. In some embodiments, the present disclosure provides methods of treating cancer comprising: screening to identify a subject with an AKT activated cancer; and administering to the subject in need thereof Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof.

[0327] In some aspects, the present disclosure provides methods of treating an AKT activated cancer comprising, administering to a subject in need thereof Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides methods of treating cancer comprising: identifying a subject with an AKT activated cancer; and administering to the subject in need thereof Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides methods of treating cancer comprising: selecting a subject with an AKT activated cancer; and administering to the subject in need thereof Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides methods of treating cancer comprising: screening to identify a subject with an AKT activated cancer; and administering to the subject in needWSGR Docket No. 61402-725.601thereof Compound A or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has a relapsed or refractory cancer after receiving at least one prior treatment. In some embodiments, the subject has a relapsed cancer after receiving at least one prior treatment. In some embodiments, the subject has a refractory cancer after receiving at least one prior treatment. In some embodiments, the at least one prior treatment comprises from a CDK2 inhibitor, a CDK4 / 6 inhibitor, an aromatase inhibitor, an anti -androgen, an androgen synthesis inhibitor, an mTOR inhibitor, a PI3Kα inhibitor, a PI3Kα mutant inhibitor, a gonadotropin-releasing hormone (GnRH) agonist, a selective estrogen receptor modulator (SERM), a selective estrogen receptor degrader (SERD), or a combination thereof. In some embodiments, the at least one prior treatment is selected from surgery, radiation, chemotherapy, and a combination thereof. In some embodiments, the at least one prior treatment is selected from surgery, radiation, and chemotherapy.

[0328] In some embodiments, the at least one prior treatment is radiation.

[0329] In some embodiments, the at least one prior treatment is chemotherapy. In some embodiments, the chemotherapy is selected from a platinum-based chemotherapy, a poly-ADP-ribose polymerase (PARP) inhibitor, a CDK4 / 6 inhibitor, an aromatase inhibitor, an antiandrogen, an androgen synthesis inhibitor, an mTOR inhibitor, a PI3Kα inhibitor, a PI3Kα mutant inhibitor, a gonadotropin-releasing hormone (GnRH) agonist, a selective estrogen receptor modulator (SERM), and a selective estrogen receptor degrader (SERD). In some embodiments, the chemotherapy is selected from a CDK2 inhibitor, a CDK4 / 6 inhibitor, an aromatase inhibitor, an anti-androgen, an androgen synthesis inhibitor, an mTOR inhibitor, a PI3Kα inhibitor, a PI3Kα mutant inhibitor, a gonadotropin-releasing hormone (GnRH) agonist, a selective estrogen receptor modulator (SERM), a selective estrogen receptor degrader (SERD, and a combination thereof. In some embodiments, the chemotherapy is selected from a CDK2 inhibitor, a CDK4 / 6 inhibitor, an aromatase inhibitor, an anti-androgen, and a selective estrogen receptor degrader (SERD). In some embodiments, the chemotherapy is a CDK2 inhibitor. In some embodiments, the chemotherapy is a CDK4 / 6 inhibitor. In some embodiments, the chemotherapy is an aromatase inhibitor. In some embodiments, the chemotherapy is an antiandrogen. In some embodiments, the chemotherapy is a selective estrogen receptor degrader (SERD). In some embodiments, the chemotherapy is a platinum-based chemotherapy. In some embodiments, the chemotherapy is a poly-ADP-ribose polymerase (PARP) inhibitor.

[0330] In some embodiments, the at least one prior treatment is surgery. In some embodiments, the surgery is a complete resection or a partial resection. In some embodiments, the surgery is a complete resection. In some embodiments, the surgery is a partial resection.WSGR Docket No. 61402-725.601

[0331] In some embodiments, the AKT activated cancer is a solid tumor. In some embodiments, the AKT activated cancer is selected from breast cancer, kidney cancer, prostate cancer, head and neck cancer, gastric cancer, lung cancer, endometrial cancer, ovarian cancer, cervical cancer, esophageal cancer, and colon cancer. In some embodiments, the AKT activated cancer is breast cancer. In some embodiments, the breast cancer is ER+ / HER2- breast cancer. In some embodiments, the breast cancer is triple negative breast cancer. In some embodiments, the AKT activated cancer is kidney cancer. In some embodiments, the kidney cancer is renal cell carcinoma. In some embodiments, the AKT activated cancer is prostate cancer. In some embodiments, the prostate cancer is castration resistant prostate cancer. In some embodiments, the AKT activated cancer is head and neck cancer. In some embodiments, the head and neck cancer is head and neck squamous cell carcinoma. In some embodiments, the AKT activated cancer is gastric cancer. In some embodiments, the AKT activated cancer is lung cancer. In some embodiments, the lung cancer is squamous cell lung cancer. In some embodiments, the AKT activated cancer is endometrial cancer. In some embodiments, the AKT activated cancer is colon cancer. In some embodiments, the colon cancer is colorectal cancer. In some embodiments, the AKT activated cancer is ovarian cancer. In some embodiments, the AKT activated cancer is cervical cancer. In some embodiments, the AKT activated cancer is esophageal cancer. In some embodiments, the esophageal cancer is squamous cell esophageal cancer.

[0332] Methods for combination treatment

[0333] In some aspects, the present disclosure provides a combination useful for the treatment of cancer. In some embodiments, the combination comprises an AKT1 selective inhibitor and a second agent. In some embodiments, the combination comprises a AKT1 selective inhibitor and a second agent selected from a CDK2 inhibitor, a CDK4 / 6 inhibitor, an aromatase inhibitor, an anti-androgen, an androgen synthesis inhibitor, an mTOR inhibitor, a PI3Kα inhibitor, a PI3Kα mutant inhibitor, a gonadotropin-releasing hormone (GnRH) agonist, a selective estrogen receptor modulator (SERM), and a selective estrogen receptor degrader (SERD). In some embodiments, the combination comprises Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof and a second agent. In some embodiments, the combination comprises Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof and a second agent selected from a CDK2 inhibitor, a CDK4 / 6 inhibitor, an aromatase inhibitor, an anti-androgen, an androgen synthesis inhibitor, an mTOR inhibitor, a PI3Kα inhibitor, a PI3Kα mutant inhibitor, a gonadotropin-releasing hormone (GnRH) agonist, a selective estrogen receptor modulator (SERM), and a selective estrogen receptor degrader (SERD). In some embodiments, the combination comprises Compound A or a pharmaceutically acceptable saltWSGR Docket No. 61402-725.601thereof and a second agent. In some embodiments, the combination comprises Compound A or a pharmaceutically acceptable salt thereof and a second agent selected from a CDK2 inhibitor, a CDK4 / 6 inhibitor, an aromatase inhibitor, an anti -androgen, an androgen synthesis inhibitor, an mTOR inhibitor, a PI3Kα inhibitor, a PI3Kα mutant inhibitor, a gonadotropin-releasing hormone (GnRH) agonist, a selective estrogen receptor modulator (SERM), and a selective estrogen receptor degrader (SERD).

[0334] In some aspects, the present disclosure provides a composition useful for the treatment of cancer. In some embodiments, the composition comprises an AKT1 selective inhibitor and a second agent. In some embodiments, the composition comprises a AKT1 selective inhibitor and a second agent selected from a CDK2 inhibitor, a CDK4 / 6 inhibitor, an aromatase inhibitor, an anti-androgen, an androgen synthesis inhibitor, an mTOR inhibitor, a PI3Kα inhibitor, a PI3Kα mutant inhibitor, a gonadotropin-releasing hormone (GnRH) agonist, a selective estrogen receptor modulator (SERM), and a selective estrogen receptor degrader (SERD). In some embodiments, the composition comprises Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof and a second agent. In some embodiments, the composition comprises Compound A, B, C, or D, or a pharmaceutically acceptable salt of any one thereof and a second agent selected from a CDK2 inhibitor, a CDK4 / 6 inhibitor, an aromatase inhibitor, an anti-androgen, an androgen synthesis inhibitor, an mTOR inhibitor, a PI3Kα inhibitor, a PI3Kα mutant inhibitor, a gonadotropin-releasing hormone (GnRH) agonist, a selective estrogen receptor modulator (SERM), and a selective estrogen receptor degrader (SERD). In some embodiments, the composition comprises Compound A or a pharmaceutically acceptable salt thereof and a second agent. In some embodiments, the composition comprises Compound A or a pharmaceutically acceptable salt thereof and a second agent selected from a CDK2 inhibitor, a CDK4 / 6 inhibitor, an aromatase inhibitor, an anti -androgen, an androgen synthesis inhibitor, an mTOR inhibitor, a PI3Kα inhibitor, a PI3Kα mutant inhibitor, a gonadotropin-releasing hormone (GnRH) agonist, a selective estrogen receptor modulator (SERM), and a selective estrogen receptor degrader (SERD).

[0335] In some aspects, the present disclosure provides methods of treating cancer comprising, administering to a subject in need thereof an AKT1 selective inhibitor and a second agent selected from a CDK2 inhibitor, a CDK4 / 6 inhibitor, an aromatase inhibitor, an anti -androgen, an androgen synthesis inhibitor, an mTOR inhibitor, a PI3Kα inhibitor, a PI3Kα mutant inhibitor, a gonadotropin-releasing hormone (GnRH) agonist, a selective estrogen receptor modulator (SERM), and a selective estrogen receptor degrader (SERD). In some embodiments, the subject is administered a second agent selected from a CDK2 inhibitor, a CDK4 / 6 inhibitor, an aromatase inhibitor, or an anti-androgen, and a SERD. In some embodiments, the SERD isWSGR Docket No. 61402-725.601selected from imlunestrant, Camizestrant, fulvestrant and elacestrant. In some embodiments, the SERD is imlunestrant. In some embodiments, the SERD is Camizestrant. In some embodiments, the SERD is fulvestrant. In some embodiments, the SERD is elacestrant.

[0336] In some aspects, the present disclosure provides methods of treating cancer comprising, administering to a subject in need thereof Compound A, B, C, or D, or a pharmaceutically acceptable salt thereof and a second agent selected from a CDK2 inhibitor, a CDK4 / 6 inhibitor, an aromatase inhibitor, an anti-androgen, an androgen synthesis inhibitor, an mTOR inhibitor, a PI3Kα inhibitor, a PI3Kα mutant inhibitor, a gonadotropin-releasing hormone (GnRH) agonist, a selective estrogen receptor modulator (SERM), and a selective estrogen receptor degrader (SERD). In some embodiments, the subject is administered a second agent selected from a CDK2 inhibitor, a CDK4 / 6 inhibitor, an aromatase inhibitor, or an anti-androgen, and a SERD. In some embodiments, the SERD is selected from imlunestrant, Camizestrant, fulvestrant and elacestrant. In some embodiments, the SERD is imlunestrant. In some embodiments, the SERD is Camizestrant. In some embodiments, the SERD is fulvestrant. In some embodiments, the SERD is elacestrant.

[0337] In some aspects, the present disclosure provides methods of treating cancer comprising, administering to a subject in need thereof Compound A or a pharmaceutically acceptable salt thereof and a second agent selected from a CDK2 inhibitor, a CDK4 / 6 inhibitor, an aromatase inhibitor, an anti-androgen, an androgen synthesis inhibitor, an mTOR inhibitor, a PI3Kα inhibitor, a PI3Kα mutant inhibitor, a gonadotropin-releasing hormone (GnRH) agonist, a selective estrogen receptor modulator (SERM), and a selective estrogen receptor degrader (SERD). In some embodiments, the subject is administered a second agent selected from a CDK2 inhibitor, a CDK4 / 6 inhibitor, an aromatase inhibitor, or an anti-androgen, and a SERD. In some embodiments, the SERD is selected from imlunestrant, Camizestrant, fulvestrant and elacestrant. In some embodiments, the SERD is imlunestrant. In some embodiments, the SERD is Camizestrant. In some embodiments, the SERD is fulvestrant. In some embodiments, the SERD is elacestrant.

[0338] In some embodiments, the cancer is a cancer having at least one mutation in the PI3K / AKT / PTEN signaling pathway, a PTEN loss of function cancer, a PTEN deficient cancer, a PTEN mutated cancer, or a PTEN altered cancer.EXAMPLES

[0339] The invention now being generally described, it will be more readily understood by reference to the following examples which are included merely for purposes of illustration ofWSGR Docket No. 61402-725.601certain aspects and embodiments of the present invention, and are not intended to limit the invention in any way.

[0340] The following synthetic schemes are provided for purposes of illustration, not limitation. The following examples illustrate the various methods of making compounds described herein. It is understood that one skilled in the art may be able to make these compounds by similar methods or by combining other methods known to one skilled in the art. It is also understood that one skilled in the art would be able to make, in a similar manner as described below by using the appropriate starting materials and modifying the synthetic route as needed. In general, starting materials and reagents can be obtained from commercial vendors or synthesized according to sources known to those skilled in the art or prepared as described herein.

[0341] The invention will now be illustrated by the following non-limiting Examples in which, unless stated otherwise.

[0342] Example 1 - Materials and Methods

[0343] Compounds: Compounds A, B, C, and D were synthesized as described in W02025081045. Compound D was synthesized analogously as described in WO2025217330. Compound D: Observed mass (ESI): 710.45 [M+H]+. 'H-NMR (400 MHz, DMSO-d6) 8 (ppm): 8.21 - 8.30 (m, 1H), 8.10 - 8.20 (m, 1H), 7.95 - 8.05 (m, 1H), 7.75 - 7.82 (m, 1H), 7.50 - 7.60 (m, 1H), 7.38 - 7.48 (m, 1H), 7.30 - 7.38 (m, 1H), 7.15 - 7.30 (m, 2H), 6.75 - 6.90 (m, 1H), 6.35 - 6.45 (m, 1H), 6.15 - 6.25 (m, 1H), 6.05 - 6.15 (m, 1H), 5.72 - 5.80 (m, 1H), 5.62 - 5.72 (m, 1H), 4.35 - 4.50 (m, 1H), 4.20 - 4.35 (m, 1H), 3.90 - 4.10 (m, 1H), 3.66 (s, 3H), 3.30 - 3.40 (m, 4H), 3.15 - 3.25 (m, 5H), 2.90 - 3.10 (m, 2H), 2.75 - 2.90 (m, 2H), 2.40 - 2.46 (m, 1H), 1.95 -2.08 (m, 1H), 1.80 - 1.95 (m, 2H), 1.25 - 1.40 (m, 2H).

[0344] Capivasertib, inavolisib, STX-478, and fulvestrant were commercially sourced.Compounds A, B, C, and D were formulated using 20% v / v propylene glycol, 20% v / v PEG 300, and 60% v / v water, with a pH of 3.0 ± 0.2. The formulations for the other compounds are as follows: capivasertib was prepared with 10% v / v DMSO, 22.5% w / w (2-Hydroxypropyl)-P-cyclodextrin (HP-P-CD), and 67.5% w / w water; fulvestrant was formulated in 100% peanut oil; inavolisib was prepared with 0.2% v / v Tween-80, 0.5% w / v methylcellulose (4,000 cp), and 99.3% w / v water; STX-478 was formulated with 30% 2-hydroxypropyl-beta-cyclodextrin and 70% w / w water, adjusted to pH 8 with IN NaOH.

[0345] Cell lines: Human cell lines used for CDX model establishment are summarized in the table below (Table 1). The BT-474, MCF-7, ZR-75-1, T47D, HCC1954, 786-0, AN3CA, and SK-UT-1 cell lines were obtained from the American Type Collection (ATCC); the KPL-4 and CAL-33 lines were sourced from CoBioer; The IGROV-1 line was obtained from NIH and the LAPC4-CR line was a gift from Dr. Michael C. Haffner. Cells were maintained as adherent cellsWSGR Docket No. 61402-725.601in DMEM (for BT-474, MCF-7, T47D, and CAL-33), EMEM (for AN3CA and SK-UT-1) or RPMI 1640 medium (for ZR-75-1, HCC1954, KPL-4, 786-0, LAPC4-CR, IGROV-1 and MKN1) supplemented with fetal bovine serum (FBS), with the exception of LAPC4-CR which was supplemented with charcoal-stripped fetal bovine serum (CS-FBS). Specific media supplements included insulin for BT-474, GlutaMAX for LAPC4-CR, and L-glutamine for CAL-33. All cultures were incubated at 37 °C in humidified atmosphere with 5% CO2.

[0346] Table 1: Summary of human cancer cell lines and experimental parameters for CDX model establishmentWSGR Docket No. 61402-725.601

[0347] Experimental Animals and Xenograft Models

[0348] Specific pathogen-free, 6-8-week-old female BALB / c Nude, NOD SCID, and NPG mice, as well as 6-8-week-old male Athymic Nude - Foxnlnu mice, were used for the establishment of the xenograft models, as shown in Table 1. Mice were housed in polycarbonate cages under controlled environmental conditions, maintaining a temperature of 23 ± 3 °C, humidity levels between 40% and 70%, and a 12-hour light / dark cycle. They had ad libitum access to food and water and were identified using ear coding.

[0349] For the cell line-derived xenograft (CDX) models, cells were typically mixed 1: 1 with Matrigel for inoculation. For the ZR-75-1 orthotopic model, cells were inoculated into the 3rd mammary fat pad of female mice. For the remaining ectopic models, cells were subcutaneously inoculated into the right flank of each mouse as indicated in Table 1. For estrogen-dependent lines (BT-474, MCF-7, ZR-75-1, and T47D), 17-P-estradiol pellets were implanted subcutaneously prior to cell inoculation to support tumor growth.

[0350] Specific pathogen-free, 4-8-week-old female Athymic Nude NU(Ncr)-Foxnlnu mice were used in three patient-derived xenograft (PDX) models: CTG-2810 (Champions Oncology), HBCx-3 (Xentech), and ST3632 (Xenostart) are ER+, PR+, HER2- breast cancer models, while HBCx-2 (Xentech) represents a triple-negative breast cancer (TNBC) model. Mice were subcutaneously implanted with tumor fragments in the left flank to establish the PDX models.

[0351] Pharmacokinetic and Pharmacodynamic (PKPD) Studies

[0352] PK / PD Studies were conducted in BT-474 and / or LAPC4-CR Xenograft Models

[0353] When tumors reached approximately 300-500 mm3, mice were randomized into vehicle and treatment groups (n=4-6 per group) and administered a single dose of the study compound. All compounds were dosed orally via gavage. At designated time points and dose levels, animals were euthanized for sample collection. Tumor tissues were snap-frozen in liquid nitrogen and stored at -80 °C. Whole blood was collected via the retro-orbital venous sinus or tail nick into K2-EDTA tubes to prepare plasma.WSGR Docket No. 61402-725.601

[0354] Dose-Range Study:

[0355] For the dose-range assessment, all samples were collected 4 hours post-dose. Dose levels were as follows:

[0356] Compound A: 1, 3, 10, 30, 60, 120, and 240 mg / kg in the BT-474 model, with an additional 0.3 mg / kg dose included for the LAPC4-CR model.

[0357] Compound B: 0.3, 1, 3, 10, 30, 90, and 180 mg / kg in both the BT-474 and LAPC4-CR models.

[0358] Compound C: 15 and 60 mg / kg in the LAPC4-CR model.

[0359] Time-Course Study:

[0360] In the time-course study, samples were collected at 4, 24, 48, and 72 hours post-dose using one or two dose levels.

[0361] Additionally, terminal PK / PD was evaluated in the BT-474 model following 21 days of treatment. Compound A (30 or 60 mg / kg) was compared against inavolisib (25 or 50 mg / kg) and capivasertib (150 mg / kg). For this study, samples were collected 4 and 8 hours after the final dose on day 21.

[0362] Efficacy Studies

[0363] Tumor volumes and body weights were recorded twice weekly. Volume was calculated using the formula: Tumor Volume (mm3) = (length x width2) / 2 where length and width are long and short diameters of a tumor, respectively. For the CTG-2810 PDX model specifically, the formula Tumor Volume (mm3) = 0.52*(length x width2) was used.

[0364] For CDX models, mice were randomized (n=8-10 / group) once mean tumor volumes reached 150-200 mm3. Treatment typically lasted 21 days, though the MCF-7 and BT-474 fulvestrant combination studies extended to 32 and 28 days, respectively. For PDX models, Athymic Nude mice were randomized (n=6-8 / group) at tumor volumes of 100-200 mm3. In the HBCx-2 PDX model, mice received the final dose on Day 21, with monitoring continuing through Day 35. In the model of MCF-7, in which Compound A in combination with palbociclib was tested, mice received the final dose was on Day 43, with monitoring continuing through Day 87.

[0365] Dosing and Regimen

[0366] Compound A: 7.5 to 120 mg / kg QD or 7.5 to 60 mg / kg BID.

[0367] Compound B: 10 to 180 mg / kg QD or 5 to 90 mg / kg BID.

[0368] Compound C: 15 or 60 mg / kg QD.

[0369] Compound D: 5, 15, or 30 mg / kg QD.

[0370] Capivasertib: 75 or 150 mg / kg BID on a 4-days-on / 3-days-off schedule for 3-4 weeks (dosed BID daily in the LAPC4-CR model).WSGR Docket No. 61402-725.601

[0371] Inavolisib: 25 or 50 mg / kg QD.

[0372] STX-478: 50 or 100 mg / kg QD.

[0373] RLY-2608: 100 mg / kg BID.

[0374] Palbociclib: 50 mg / kg QD.

[0375] CDK2i: 55 or 109 mg / kg QD.

[0376] All compounds above were dosed orally.

[0377] Fulvestrant (s.c.): 50 mg / kg on Days 1, 3, and 8, followed by 25 mg / kg twice weekly from Day 10 onward.

[0378] In combination settings, fulvestrant was administered 2 hours prior to Compound A in MCF-7 and BT-474 models. Similarly, STX-478 was administered 2 hours prior to Compound A in CAL-33 and HCC1954 models.

[0379] Non-Fasting Glucose

[0380] In the BT-474 model studies, animals had free access to a normal diet throughout the study period. Blood glucose levels were measured for four to five animals per group at 1, 4, 7.5, and 24 hours following morning dosing on Day 20 for Compounds A, B, and capivasertib. For Compound C, additional measurements were taken at 0.5, 2, 9, and 12 hours. Blood samples were obtained via tail lancet puncture, and glucose concentrations were determined using an Accu-Chek Guide.

[0381] Plasma Sample Processing for Compound Exposure

[0382] At indicated time points post-dose, blood was collected via cardiac puncture into EDTA-K2 tubes. The sample was centrifuged at 4000 ref for 5 minutes at 4°C. Plasma was collected and then store at -80°C ± 5°C.

[0383] Plasma samples were diluted 10-fold with blank mouse plasma. A 20 pL aliquot of diluted plasma was treated with 30 pL of 4% formic acid in water. After shaking for 20 seconds, the samples were incubated at 37°C for 25 minutes. All samples were extracted with 180 pL of 90% acetonitrile with 5 mM ammonium acetate and 0.1% acetic acid containing the internal standard (Verapamil). The mixture was shaken on a shaker for 15 minutes and subsequently centrifuged at 3220 g for 15 minutes. A 150 pL aliquot of the supernatant was transferred for analysis by LC- MS / MS. Calibration standards and quality control samples were prepared by spiking the test compounds into blank mouse plasma followed by incubation at 37 °C for 15 minutes and then processed by the same procedure as the unknown samples in the same batch.

[0384] Protein Extraction for Western Blot Analysis

[0385] Frozen tumor tissue (40 mg) was homogenized in 600 pL RIPA buffer using a QIAGEN™ TissueLyser-II (30 Hz for 3 min at 4°C). Lysates were centrifuged at 12,000 xg forWSGR Docket No. 61402-725.60115 min at 4°C. Supernatants were collected, diluted 1: 1 with cold RIP A buffer, and mixed for 30 min at 4°C before a final centrifugation (12,000 xg, 15 min). Samples were stored at -80°C.

[0386] Protein concentrations were determined by BCA assay. Standards (0-2 mg / mL) and diluted lysates were incubated with working reagent at 37°C for 30 min. Absorbance was measured at 562 nm, and sample concentrations were calculated against the standard curve to ensure equal loading for downstream applications.

[0387] Normalized lysates were resolved by SDS-PAGE at 120V and transferred to nitrocellulose membranes (0.3 A for 1.5 h). Membranes were blocked for 1 h at room temperature and incubated overnight at 4°C with primary antibodies:

[0388] Total / Phospho-AKTl: Aktl (CST #2938) and p-Aktl Ser473 (CST #9018)

[0389] Total / Phospho-AKT2: Akt2 (CST #3063) and p-Akt2 Ser474 (CST #8599)

[0390] Following IX TBST washes, membranes were incubated with IRDye 800CW or 680CW secondary antibodies (Li-COR) for 1 h at room temperature.

[0391] Blots were imaged on an Odyssey CLx scanner. Band densitometry and background subtraction were performed using Image Studio. Target protein expression was normalized to controls, and relative expression was calculated as the ratio of target density to control density.

[0392] Protein Extraction for Homogeneous Time-Resolved Fluorescence (HTRF) analysis

[0393] Frozen tumors were thawed on ice and homogenized in 500 pL of IX RIPA buffer (containing 2X protease / phosphatase inhibitors) using a QIAGEN™ TissueLyser-II (20 Hz for 5 min, twice). Lysates were centrifuged at 20,000 xg for 10 min at 4°C. The supernatant was collected and centrifuged again for 20 min at 20,000 xg. The final clear supernatant was transferred to a 96-well deep-well plate on ice. Protein concentrations were normalized via BCA assay.

[0394] HTRF Assay Protocol

[0395] Levels of total and phosphorylated AKT (tAKT / pAKTl S473 and tAKT2 / pAKT2 S474) were quantified using Revvity™ HTRF kits according to the manufacturer’s instructions.Revvity™ HTRF kits include tAKT (64NKTPEH), and pAKTl S473 (63 ADK078PEH), tAKT2 (63ADK081PEH), and pAKT2 S473 (63ADK080PEH).

[0396] Normalized lysates were diluted to IX HTRF lysis buffer. Antibody cocktails were prepared by mixing d2 and Eu antibodies in detection buffer. Using Integra multichannel pipettors, 16 pL of lysate and 4 pL of antibody mixture were combined in a 384-well plate. Plates were sealed, centrifuged at 300 xg, and incubated overnight at 4°C. Following a final centrifugation, fluorescence was measured on a Pherastar plate reader at 665 nm and 620 nm. Raw HTRF data were processed by subtracting negative control (background) values. Samples were analyzed in triplicate. Data were normalized to the vehicle group, and phospho-signalsWSGR Docket No. 61402-725.601were expressed as a ratio of the corresponding total protein (pAKTl / tAKT or pAKT2 / tAKT2) to account for total protein levels.

[0397] Data analysis

[0398] In Vivo IC50 calculation

[0399] In the PKPD studies, raw plasma pharmacokinetic (PK) data were analyzed in GraphPad™ Prism 10 along with corresponding pharmacodynamic (PD) Western blot data. The in vivo ICso was determined using a nonlinear regression curve fit with the built-in equation for inhibitor versus response (variable slope, four parameters).

[0400] Tumor Growth Inhibition

[0401] Inhibition of tumor growth was determined by calculating the percent TGI (100% x [1-(final MTV - initial MTV of a treated group) / (final MTV - initial MTV of the control group)]). Treatment started on Day 0. Tumor volumes of treatment groups for the study's duration and at the study's completion were compared to that of the control group.

[0402] Progression Free Survival (PFS): Progression free survival was defined as the time from treatment initiation to tumor progression, where progression was defined as tumor volume exceeding the initial tumor size. Kaplan-Meier analysis plotted time to progression, with median survival defined as the time when half the mice reached progression.

[0403] In CDX models, percent of Complete Response (CR) is the percentage of mice in the same group showing CR at the last measurement, defined as a tumor volume is no more than 32 mm3.

[0404] In PDX models, a partial responder (PR) is defined as a tumor volume that is less than or equal to 30% of the volume recorded on Day 0 for two consecutive measurements.

[0405] Body Weight Change: Body Weight Change represents the percentage difference between the group's mean body weight on the specific treatment day and day zero, relative to the initial starting weight.

[0406] Statistical Analysis: GraphPad™ Prism 10 was used for data analysis. Data were presented as Mean ± SEM, expect that plasma concentrations were presented as Mean ± SD.

Claims

WSGR Docket No. 61402-725.601CLAIMS WHAT IS CLAIMED IS:

1. A method of treating cancer having at least one mutation in the PI3K / AKT / PTEN signaling pathway comprising, administering to a subject in need thereof an AKT1 selective inhibitor.

2. A method of treating cancer comprising:identifying a subject with at least one mutation in the PI3K / AKT / PTEN signaling pathway; andadministering to the subject an AKT1 selective inhibitor.

3. A method of treating cancer comprising:selecting a subject with at least one mutation in the PI3K / AKT / PTEN signaling pathway; andadministering to the subject an AKT1 selective inhibitor.

4. A method of treating cancer comprising:screening to identify a subject with at least one mutation in the PI3K / AKT / PTEN signaling pathway; andadministering to the subject identified in the screen an AKT1 selective inhibitor.

5. A method of treating a PTEN loss of function cancer comprising, administering to a subject in need thereof an AKT1 selective inhibitor.

6. A method of treating cancer comprising:identifying a subject with a PTEN loss of function cancer; andadministering to the subject an AKT1 selective inhibitor.

7. A method of treating cancer comprising:selecting a subject with a PTEN loss of function cancer; andadministering to the subject an AKT1 selective inhibitor.

8. A method of treating cancer comprising:screening to identify a subject with a PTEN loss of function cancer; and administering to the subject identified in the screen an AKT1 selective inhibitor.

9. A method of treating a PTEN deficient cancer comprising, administering to a subject in need thereof an AKT1 selective inhibitor.WSGR Docket No. 61402-725.60110. A method of treating cancer comprising:identifying a subject with a PTEN deficient cancer; andadministering to the subject an AKT1 selective inhibitor.

11. A method of treating cancer comprising:selecting a subject with a PTEN deficient cancer; andadministering to the subject an AKT1 selective inhibitor.

12. A method of treating cancer comprising:screening to identify a subject with a PTEN deficient cancer; andadministering to the subject identified in the screen an AKT1 selective inhibitor.

13. A method of treating a PTEN altered cancer comprising, administering to a subject in need thereof an AKT1 selective inhibitor.

14. A method of treating cancer comprising:identifying a subject with a PTEN altered cancer; andadministering to the subject an AKT1 selective inhibitor.

15. A method of treating cancer comprising:selecting a subject with a PTEN altered cancer; andadministering to the subject an AKT1 selective inhibitor.

16. A method of treating cancer comprising:screening to identify a subject with a PTEN altered cancer; andadministering to the subject identified in the screen an AKT1 selective inhibitor.

17. A method of treating a PTEN mutated cancer comprising, administering to a subject in need thereof an AKT1 selective inhibitor.

18. A method of treating cancer comprising:identifying a subject with a PTEN mutated cancer; andadministering to the subject an AKT1 selective inhibitor.

19. A method of treating cancer comprising:selecting a subject with a PTEN mutated cancer; andadministering to the subject an AKT1 selective inhibitor.

20. A method of treating cancer comprising:WSGR Docket No. 61402-725.601screening to identify a subject with a PTEN mutated cancer; andadministering to the subject identified in the screen an AKT1 selective inhibitor.

21. A method of treating cancer comprising, administering to a subject in need thereof an AKT1 selective inhibitor, wherein the subject has a relapsed or refractory cancer after receiving at least one prior treatment.

22. A method of treating cancer comprising, administering to a subject in need thereof an AKT1 selective inhibitor, wherein the subject has been previously administered a selective estrogen receptor degrader (SERD).

23. A method of treating cancer comprising, administering to a subject in need thereof an AKT1 selective inhibitor, wherein the subject has been previously administered an aromatase inhibitor.

24. A method of treating cancer comprising, administering to a subject in need thereof an AKT1 selective inhibitor, wherein the subject has been previously administered a CDK4 / 6 inhibitor.

25. A method of treating cancer comprising, administering to a subject in need thereof an AKT1 selective inhibitor, wherein the subject has been previously administered an antiandrogen.

26. A method of treating cancer comprising, administering to a subject in need thereof an AKT1 selective inhibitor, wherein the subject has been previously administered a selective estrogen receptor degrader (SERD) and a CDK4 / 6 inhibitor.

27. A method of treating cancer comprising, administering to a subject in need thereof an AKT1 selective inhibitor, wherein the subject has been previously administered an aromatase inhibitor and a CDK4 / 6 inhibitor.

28. A method of treating cancer comprising, administering to a subject in need thereof an AKT1 selective inhibitor and a second agent selected from a CDK2 inhibitor, a CDK4 / 6 inhibitor, an aromatase inhibitor, an anti-androgen, an androgen synthesis inhibitor, an mTOR inhibitor, a PI3Ka inhibitor, a PI3Ka mutant inhibitor, a gonadotropin-releasing hormone (GnRH) agonist, a selective estrogen receptor modulator (SERM), and a selective estrogen receptor degrader (SERD).WSGR Docket No. 61402-725.60129. A method of treating cancer having at least one mutation in the PI3K / AKT / PTEN signaling pathway comprising, administering to a subject in need thereof (S)-l-(4-((5-(2-(2-aminopyridin-3-yl)-5-(lH-pyrazol-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-lH-inden-l-yl)amino)piperidin-l-yl)prop-2-en-l-one or a pharmaceutically acceptable salt thereof.

30. A method of treating cancer comprising:identifying a subject with at least one mutation in the PI3K / AKT / PTEN signaling pathway; andadministering to the subject (S)-l-(4-((5-(2-(2-aminopyridin-3-yl)-5-(lH-pyrazol-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-lH-inden-l-yl)amino)piperidin-l-yl)prop-2-en-l-one or a pharmaceutically acceptable salt thereof.

31. A method of treating cancer comprising:selecting a subject with at least one mutation in the PI3K / AKT / PTEN signaling pathway; andadministering to the subject (S)-l-(4-((5-(2-(2-aminopyridin-3-yl)-5-(lH-pyrazol-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-lH-inden-l-yl)amino)piperidin-l-yl)prop-2-en-l-one or a pharmaceutically acceptable salt thereof.

32. A method of treating cancer comprising:screening to identify a subject with at least one mutation in the PI3K / AKT / PTEN signaling pathway; andadministering to the subject identified in the screen (S)-l-(4-((5-(2-(2-aminopyridin-3-yl)-5-(lH-pyrazol-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-lH-inden-l-yl)amino)piperidin-l-yl)prop-2-en-l-one or a pharmaceutically acceptable salt thereof.

33. A method of treating a PTEN mutated cancer comprising, administering to a subject in need thereof (S)-1-(4-((5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)piperidin-1-yl)prop-2-en-1-one or a pharmaceutically acceptable salt thereof.

34. A method of treating cancer comprising:identifying a subject with a PTEN mutated cancer; andadministering to the subject (S)-l-(4-((5-(2-(2-aminopyridin-3-yl)-5-(lH-pyrazol-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-lH-inden-l-yl)amino)piperidin-l-yl)prop-2-en-l-one or a pharmaceutically acceptable salt thereof.WSGR Docket No. 61402-725.60135. A method of treating cancer comprising:selecting a subject with a PTEN mutated cancer; andadministering to the subject (S)-l-(4-((5-(2-(2-aminopyridin-3-yl)-5-(lH-pyrazol-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-lH-inden-l-yl)amino)piperidin-l-yl)prop-2-en-l-one or a pharmaceutically acceptable salt thereof.

36. A method of treating cancer comprising:screening to identify a subject with a PTEN mutated cancer; andadministering to the subject identified in the screen (S)-l-(4-((5-(2-(2-aminopyridin-3-yl)-5-(lH-pyrazol-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-lH-inden-l-yl)amino)piperidin-l-yl)prop-2-en-l-one or a pharmaceutically acceptable salt thereof.

37. A method of treating a PTEN loss of function cancer comprising, administering to a subject in need thereof (S)-1-(4-((5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)piperidin-1-yl)prop-2-en-1-one or a pharmaceutically acceptable salt thereof.

38. A method of treating cancer comprising:identifying a subject with a PTEN loss of function cancer; andadministering to the subject (S)-l-(4-((5-(2-(2-aminopyridin-3-yl)-5-(lH-pyrazol-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-lH-inden-l-yl)amino)piperidin-l-yl)prop-2-en-l-one or a pharmaceutically acceptable salt thereof.

39. A method of treating cancer comprising:selecting a subject with a PTEN loss of function cancer; andadministering to the subject (S)-l-(4-((5-(2-(2-aminopyridin-3-yl)-5-(lH-pyrazol-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-lH-inden-l-yl)amino)piperidin-l-yl)prop-2-en-l-one or a pharmaceutically acceptable salt thereof.

40. A method of treating cancer comprising:screening to identify a subject with a PTEN loss of function cancer; and administering to the subject identified in the screen (S)-l-(4-((5-(2-(2-aminopyridin-3-yl)-5-(lH-pyrazol-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-lH-inden-l-yl)amino)piperidin-l-yl)prop-2-en-l-one or a pharmaceutically acceptable salt thereof.

41. A method of treating a PTEN deficient cancer comprising, administering to a subject in need thereof (S)-l-(4-((5-(2-(2-aminopyridin-3-yl)-5-(lH-pyrazol-l-yl)-3H-imidazo[4,5-WSGR Docket No. 61402-725.601b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)piperidin-1-yl)prop-2-en-1-one or a pharmaceutically acceptable salt thereof.

42. A method of treating cancer comprising:identifying a subject with a PTEN deficient cancer; andadministering to the subject (S)-l-(4-((5-(2-(2-aminopyridin-3-yl)-5-(lH-pyrazol-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-lH-inden-l-yl)amino)piperidin-l-yl)prop-2-en-l-one or a pharmaceutically acceptable salt thereof.

43. A method of treating cancer comprising:selecting a subject with a PTEN deficient cancer; andadministering to the subject (S)-l-(4-((5-(2-(2-aminopyridin-3-yl)-5-(lH-pyrazol-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-lH-inden-l-yl)amino)piperidin-l-yl)prop-2-en-l-one or a pharmaceutically acceptable salt thereof.

44. A method of treating cancer comprising:screening to identify a subject with a PTEN deficient cancer; andadministering to the subject identified in the screen (S)-l-(4-((5-(2-(2-aminopyridin-3-yl)-5-(lH-pyrazol-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-lH-inden-l-yl)amino)piperidin-l-yl)prop-2-en-l-one or a pharmaceutically acceptable salt thereof.

45. A method of treating a PTEN altered cancer comprising, administering to a subject in need thereof (S)-l-(4-((5-(2-(2-aminopyridin-3-yl)-5-(lH-pyrazol-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)piperidin-1-yl)prop-2-en-1-one or a pharmaceutically acceptable salt thereof.

46. A method of treating cancer comprising:identifying a subject with a PTEN altered cancer; andadministering to the subject (S)-l-(4-((5-(2-(2-aminopyridin-3-yl)-5-(lH-pyrazol-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-lH-inden-l-yl)amino)piperidin-l-yl)prop-2-en-l-one or a pharmaceutically acceptable salt thereof.

47. A method of treating cancer comprising:selecting a subject with a PTEN altered cancer; andadministering to the subject (S)-l-(4-((5-(2-(2-aminopyridin-3-yl)-5-(lH-pyrazol-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-lH-inden-l-yl)amino)piperidin-l-yl)prop-2-en-l-one or a pharmaceutically acceptable salt thereof.WSGR Docket No. 61402-725.60148. A method of treating cancer comprising:screening to identify a subject with a PTEN altered cancer; andadministering to the subject identified in the screen (S)-l-(4-((5-(2-(2-aminopyridin-3-yl)-5-(lH-pyrazol-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-lH-inden-l-yl)amino)piperidin-l-yl)prop-2-en-l-one or a pharmaceutically acceptable salt thereof.

49. A method of treating a PIK3CA activated cancer comprising, administering to a subject in need thereof (S)-1-(4-((5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)piperidin-1-yl)prop-2-en-1-one or a pharmaceutically acceptable salt thereof.

50. A method of treating cancer comprising:identifying a subject with a PIK3CA activated cancer; andadministering to the subject (S)-l-(4-((5-(2-(2-aminopyridin-3-yl)-5-(lH-pyrazol-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-lH-inden-l-yl)amino)piperidin-l-yl)prop-2-en-l-one or a pharmaceutically acceptable salt thereof.

51. A method of treating cancer comprising:selecting a subject with a PIK3CA activated cancer; andadministering to the subject (S)-l-(4-((5-(2-(2-aminopyridin-3-yl)-5-(lH-pyrazol-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-lH-inden-l-yl)amino)piperidin-l-yl)prop-2-en-l-one or a pharmaceutically acceptable salt thereof.

52. A method of treating cancer comprising:screening to identify a subject with a PIK3CA activated cancer; andadministering to the subject identified in the screen (S)-l-(4-((5-(2-(2-aminopyridin-3-yl)-5-(lH-pyrazol-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-lH-inden-l-yl)amino)piperidin-l-yl)prop-2-en-l-one or a pharmaceutically acceptable salt thereof.

53. A method of treating a AKT activated cancer comprising, administering to a subject in need thereof (S)-1-(4-((5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)piperidin-1-yl)prop-2-en-1-one or a pharmaceutically acceptable salt thereof.

54. A method of treating cancer comprising:identifying a subject with an AKT activated cancer; andWSGR Docket No. 61402-725.601administering to the subject (S)-l-(4-((5-(2-(2-aminopyridin-3-yl)-5-(lH-pyrazol-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-lH-inden-l-yl)amino)piperidin-l-yl)prop-2-en-l-one or a pharmaceutically acceptable salt thereof.

55. A method of treating cancer comprising:selecting a subject with an AKT activated cancer; andadministering to the subject (S)-l-(4-((5-(2-(2-aminopyridin-3-yl)-5-(lH-pyrazol-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-lH-inden-l-yl)amino)piperidin-l-yl)prop-2-en-l-one or a pharmaceutically acceptable salt thereof.

56. A method of treating cancer comprising:screening to identify a subject with an AKT activated cancer; andadministering to the subject identified in the screen (S)-l-(4-((5-(2-(2-aminopyridin-3-yl)-5-(lH-pyrazol-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-lH-inden-l-yl)amino)piperidin-l-yl)prop-2-en-l-one or a pharmaceutically acceptable salt thereof.

57. A method of treating cancer comprising, administering to a subject in need thereof (S)-l-(4-((5-(2-(2-aminopyridin-3-yl)-5-(lH-pyrazol-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-lH-inden-l-yl)amino)piperidin-l-yl)prop-2-en-l-one or a pharmaceutically acceptable salt thereof, wherein the subject has a relapsed or refractory cancer after receiving at least one prior treatment.

58. A method of treating cancer comprising, administering to a subject in need thereof (S)-l-(4-((5-(2-(2-aminopyridin-3-yl)-5-(lH-pyrazol-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-lH-inden-l-yl)amino)piperidin-l-yl)prop-2-en-l-one or a pharmaceutically acceptable salt thereof, wherein the subject has been previously administered a SERD.

59. A method of treating cancer comprising, administering to a subject in need thereof (S)-l-(4-((5-(2-(2-aminopyridin-3-yl)-5-(lH-pyrazol-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro- lH-inden-l-yl)amino)piperidin-l-yl)prop-2-en-l -one or a pharmaceutically acceptable salt thereof, wherein the subject has been previously administered an aromatase inhibitor.

60. A method of treating cancer comprising, administering to a subject in need thereof (S)-l-(4-((5-(2-(2-aminopyridin-3-yl)-5-(lH-pyrazol-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro- lH-inden-l-yl)amino)piperidin-l-yl)prop-2-en-l -one or a pharmaceutically acceptable salt thereof, wherein the subject has been previously administered a CDK4 / 6 inhibitor.WSGR Docket No. 61402-725.60161. A method of treating cancer comprising, administering to a subject in need thereof (S)-l-(4-((5-(2-(2-aminopyridin-3-yl)-5-(lH-pyrazol-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-lH-inden-l-yl)amino)piperidin-l-yl)prop-2-en-l-one or a pharmaceutically acceptable salt thereof, wherein the subject has been previously administered an anti -androgen.

62. A method of treating cancer comprising, administering to a subject in need thereof (S)-l-(4-((5-(2-(2-aminopyridin-3-yl)-5-(lH-pyrazol-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-lH-inden-l-yl)amino)piperidin-l-yl)prop-2-en-l-one or a pharmaceutically acceptable salt thereof, wherein the subject has been previously administered a SERD and a CDK4 / 6 inhibitor.

63. A method of treating cancer comprising, administering to a subject in need thereof (S)-l -(4-((5-(2-(2-aminopyridin-3-yl)-5-(lH-pyrazol-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-lH-inden-l-yl)amino)piperidin-l-yl)prop-2-en-l-one or a pharmaceutically acceptable salt thereof, wherein the subject has been previously administered an aromatase inhibitor and a CDK4 / 6 inhibitor.

64. A method of treating cancer comprising, administering to a subject in need thereof (S)-l-(4-((5-(2-(2-aminopyridin-3-yl)-5-(lH-pyrazol-l-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-lH-inden-l-yl)amino)piperidin-l-yl)prop-2-en-l-one or a pharmaceutically acceptable salt thereof, and a second agent selected from a CDK2 inhibitor, a CDK4 / 6 inhibitor, an aromatase inhibitor, an anti-androgen, an androgen synthesis inhibitor, an mTOR inhibitor, a PI3Ka inhibitor, a PI3Ka mutant inhibitor, a gonadotropin-releasing hormone (GnRH) agonist, a selective estrogen receptor modulator (SERM), and a selective estrogen receptor degrader (SERD).

65. The method of claim 21 or claim 57, wherein the subject has a relapsed cancer after receiving at least one prior treatment.

66. The method of claim 21 or claim 57, wherein the subject has a refractory cancer after receiving at least one prior treatment.

67. The method of any one of claims 13, 57, 65, or 66, wherein the at least one prior treatment is selected from surgery, radiation, and chemotherapy.

68. The method of claim 67, wherein the chemotherapy is selected from a CDK4 / 6 inhibitor, an aromatase inhibitor, an anti-androgen, an androgen synthesis inhibitor, an mTOR inhibitor, a PI3Ka inhibitor, a PI3Ka mutant inhibitor, a gonadotropin-releasing hormone (GnRH) agonist, aWSGR Docket No. 61402-725.601selective estrogen receptor modulator (SERM), and a selective estrogen receptor degrader (SERD).

69. The method of claim 67, wherein the chemotherapy is selected from a platinum-based chemotherapy, a poly-ADP-ribose polymerase (PARP) inhibitor, a CDK4 / 6 inhibitor, an aromatase inhibitor, an anti-androgen, an androgen synthesis inhibitor, an mTOR inhibitor, a PI3Ka inhibitor, a PI3Ka mutant inhibitor, a gonadotropin-releasing hormone (GnRH) agonist, a selective estrogen receptor modulator (SERM), and a selective estrogen receptor degrader (SERD).

70. The method of claim 67, wherein the surgery is a complete resection or a partial resection.

71. The method of any one of claims 1-70, wherein the cancer is a solid tumor.

72. The method of any one of claims 1-71, wherein the cancer is selected from breast cancer, kidney cancer, prostate cancer, head and neck cancer, gastric cancer, lung cancer, endometrial cancer, ovarian cancer, cervical cancer, esophageal cancer, and colon cancer.

73. The method of claim 72, wherein the cancer is breast cancer.

74. The method of claim 73, wherein the breast cancer is ER+ / HER2- breast cancer.

75. The method of claim 73, wherein the breast cancer is triple negative breast cancer.

76. The method of claim 72, wherein the cancer is kidney cancer.

77. The method of claim 76, wherein the kidney cancer is renal cell carcinoma.

78. The method of claim 72, wherein the cancer is prostate cancer.

79. The method of claim 78, wherein the prostate cancer is castration resistant prostate cancer.

80. The method of claim 72, wherein the cancer is head and neck cancer.

81. The method of claim 80, wherein the head and neck cancer is head and neck squamous cell carcinoma.

82. The method of claim 72, wherein the cancer is gastric cancer.WSGR Docket No. 61402-725.60183. The method of claim 72, wherein the cancer is lung cancer.

84. The method of claim 83, wherein the lung cancer is squamous cell lung cancer.

85. The method of claim 72, wherein the cancer is endometrial cancer.

86. The method of claim 72, wherein the cancer is colon cancer.

87. The method of claim 86, wherein the colon cancer is colorectal cancer.

88. The method of claim 72, wherein the cancer is ovarian cancer.

89. The method of claim 72, wherein the cancer is cervical cancer.

90. The method of claim 72, wherein the cancer is esophageal cancer.

91. The method of claim 90, wherein the esophageal cancer is squamous cell esophageal cancer.

92. The method of any one of claims 1-20 or 29-56, wherein the subject is administered a second agent selected from a CDK2 inhibitor, a CDK4 / 6 inhibitor, an aromatase inhibitor, an anti-androgen, an androgen synthesis inhibitor, an mTOR inhibitor, a PI3Ka inhibitor, a PI3Ka mutant inhibitor, a gonadotropin-releasing hormone (GnRH) agonist, a selective estrogen receptor modulator (SERM), and a selective estrogen receptor degrader (SERD).

93. The method of any one of claims 1-4 or 29-32, wherein the at least one mutation in the PI3K / AKT / PTEN signaling pathway is an insertion, a deletion, or a substitution at a residue.

94. The method of any one of claims 1-4 or 29-32, wherein the at least one mutation in the PI3K / AKT / PTEN signaling pathway is a PIK3CA mutation.

95. The method of claim 94, wherein the PIK3CA mutation is at a residue selected from R88, R93, G106, K111, G118, N345, C420, E453, E542, E545, Q546, M1043, H1047, and G1049.

96. The method of claim 94, wherein the PIK3CA mutation is at a residue selected from R38, R88, R93, G106, K111, G118, C124, K342, N345, C420, E453, E542, E545, Q546, M1043, H1047, and G1049.

97. The method of any one of claims 1-4 or 29-32, wherein the at least one mutation in the PI3K / AKT / PTEN signaling pathway is a AKT1 mutation.WSGR Docket No. 61402-725.60198. The method of claim 97, wherein the AKT1 mutation is at residue E17.

99. The method of claim 97, wherein the AKT1 mutation is E17K.

100. The method of any one of claims 1-4, 17-20, or 29-36, wherein the at least one mutation in the PI3K / AKT / PTEN signaling pathway is a PTEN mutation.

101. The method of claim 100, wherein the PTEN mutation is at residue selected from D92, G129, R130, C136, and R173.

102. The method of claim 100, wherein the PTEN mutation is at residue selected from D92, L108, Y115, G129, R130, C136, Q149, and R173.

103. The method of claim 100, wherein the PTEN mutation is selected from D92E, D92Y, D92H, D92V, G129E, G129V, G129R, R130Q, R130G, R130L, R130P, C136R, R173C, and R173H.

104. The method of claim 100, wherein the PTEN mutation is selected from D92E, D92Y, D92H, D92V, L108R, Y115C, G129E, G129V, G129R, R130Q, R130G, R130L, R130P, C136R, R173C, and R173H.

105. The method of any one of claims 22, 26, 28, 58, 62, 64, or 68, wherein the SERD is selected from imlunestrant, Camizestrant, fulvestrant and elacestrant.

106. A compoundpharmaceutically acceptable salt thereof.

107. A pharmaceutical composition comprisingpharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

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