P110 inhibitors for the treatment of cancer

Abstract

Provided herein, in some embodiments, are methods ofusingpl 10 inhibitors in the treatment of a cancer comprising a gain of function mutation of a PIK3CA gene.

Description

WSGR Ref: 64162-710.601 p110 INHIBITORS FOR THE TREATMENT OF CANCER CROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims priority to U.S. Provisional Application No. 63 / 660,800 filed June 17,2024, the disclosure of which is hereby incorporated by reference in its entirety.BACKGROUND

[0002] The Phosphoinositide 3-kinase (PI3K) pathway may play an important role in many biologicalprocesses, including cell cycle progression, cell growth, survival, actin rearrangement and migration, and intracellular vesicular transport. Class IA PI3Ks are heterodimers consisting of p85 regulatory subunit. Class IB PI3K consists ofand p101 / p84 regulatory subunits. In mammals, there are four genes, PIK3CA, PIK3CB, PIK3CG, and PIK3CD encoding p110 catalytic isoforms: , p110 , p110 , andrespectively. PI3K activation includes generation of phosphatidylinositol-3,4,5- trisphosphate (PI(3,4,5)P3) by the activated catalytic subunit, which in turn activates multiple downstream signaling events through AKT, MTOR, various transcription factors, and other signaling components. The concept of targeting specific p110 isoforms with isoform selective inhibitors is actively being explored in cancer research. Although p110 inhibitors are beingresearched for use in the treatment of cancer, resistance to p110 inhibitors as well as clinical safety and efficacy challenges remain. Accordingly, there is a need for the development of novel p110 inhibitor treatments for cancer-targeted therapies. BRIEF SUMMARY OF THE INVENTION

[0003] The present disclosure is based, in part, on the discovery that cancers may be associated with aPIK3CA genetic mutation (e.g. a gain of function mutation), and once identified, such cancers may be treated by administering (e.g., a therapeutically effective amount) p110 inhibitors. Provided herein, in some embodiments, is a method of treating a cancer in a patient in need thereof, said method comprising administering two compositions each comprising aphosphoinositide 3- p110 ; wherein said cancer has been previouslydetermined as comprising a mutation of a PIK3CA gene. In some embodiments, the mutation is a gain of function mutation. In some embodiments, said gain of function of said PIK3CA gene increases an amount, function, or signaling activity of as compared to a wild-typeamount, function, or signaling activity of .

[0004] Further provided herein, in some embodiments, is a method of treating a cancer in a subject inWSGR Ref: 64162-710.601 phosphoinositide 3- 3-WSGR Ref: 64162-710.601 (GSK-2636771).

[0005] Further provided herein, in some embodiments, is a method of treating a cancer in a subject ina synergistic effect.

[0006] Further provided herein, in some embodiments, is a method of treating a cancer in a subject ininhibitor. In some embodiments, said administering improves an activity of said mutant aid administering improves an activity exhibits a synergistic effect. In some embodiments, said synergistic effect is on inhibiting tumor growth. In some embodiments, said inhibition of tumor growth is exhibited for at least 4 days. In some embodiments, said administering inhibits tumor growth more than a corresponding administratio inhibitor. In some embodiments, said administering increases said cancer cell inhibition some embodiments, said administering increases said cancer cell inhibition compared to a inhibitor. In some embodiments, said administering increases said cancer cell inhibition compa cell inhibition is increased by at least 5%. In some embodiments, said cancer cell inhibition is increased by at least 10%. In some embodiments, said cancer cell inhibition is increased by at least 15%. In some embodiments, said cancer cell inhibition is increased by at least 25%. In some embodiments, said cancer cell inhibition is increased by at least 30%. In some embodiments, said cancer cell inhibition is increased by at least 40%. In some embodiments,said cancer cell inhibition is increased by at least 50%.

[0007] Further provided herein, in some embodiments, is a method of treating a cancer in a subject insaid subject has received or has been previously determined to receive a mutant selectiveWSGR Ref: 64162-710.601 embodiments, a tumor of said cancer was determined to increase in a size or increase in a rate of growth.

[0008] Further provided herein, in some embodiments, is a method of treating a cancer in a subject insly determined to not to increase in a size or increase in a rate of growth. In some embodiments, said mutant -478, RLY-2608, RLY-5836, LY4045004, BPI- 21668, LOXO-783, SNV-4818, inavolisib, or a combination thereof. In some embodiments, -6482, TGX-221, SAR-260301, KA-2237, AZD- 8186, GSK-2636771, PIK-108, or a combination thereof. In some embodiments, said bodiments, said cancer comprises endometrial cancer, breast cancer, cervical cancer, anal cancer, vaginal cancer, small bowel cancer, bladder cancer, colorectal cancer, head and neck cancer, small cell lung cancer, non-small cell lung cancer ovarian cancer, prostate cancer, gastric cancer, melanoma, esophogastric cancer, glioma, soft tissue sarcoma, thyroid cancer, prostate cancer, or any combination thereof. In some embodiments, said cancer comprises a mutation in a PIK3CA gene. In some embodiments, said cancer comprises a mutation in a p110 protein. In some said administering increases cancer cell inhibition. In some embodiments, said administering increases said cancer cell inhibition compared to a corresponding administration to a cancer expressing a wildtype form of p110 alpha. In some embodiments, said cancer expresses a mutat mutation. In some embodiments, said hotspot mutation comprises a H1047X mutation, a E542X mutation, a E545X mutation, or any combination thereof. In some embodiments, said is a gain of function mutant. In some embodiments, said administering increases an activity ofWSGR Ref: 64162-710.601 some embodiments, said cancer has an increased amount, function, or signaling activity of -type amount, function, or signaling activity INCORPORATION BY REFERENCE

[0009] All publications, patents, and patent applications mentioned in this specification are hereinincorporated 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. To the extent publications and patents or patent applications incorporated by reference contradict the disclosure contained in the specification, the specification is intended to supersede and / or take precedence over any such contradictory material. BRIEF DESCRIPTION OF DRAWINGS

[0010] The novel features of the invention are set forth with particularity in the appended claims. Abetter 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:

[0011] FIGs. 1A-1C illustrate the activity of p110 inhibitors in KP4 cells with and without a loss offunction (LOF) mutation in a PIK3CA gene. FIG.1A demonstrates the activity of AZD-8186, FIG.1B demonstrates the activity of GSK- FIG. 1C

[0012] FIGs. 2A-2D illustrate the activity of p110 inhibitors in cells with and without mutation in aPIK3CA gene (MDA-MB-231 -MB-453 cells: H1047R mutated ). FIG.2A demonstrates the inhibition of MDA-MB-231 and MDA-MB-453 cells when treated mutant selective inhibitor inavolisib, alone. FIG. 2B demonstrates theinhibition of MDA-MB-231 and MDA-MB-453 cells treated -selective inhibitorTGX-221 alone. FIG.2C demonstrates the inhibition of MDA-MB-231 and MDA-MB-453 cells when treated with a combination of a inavolisib, a mutant selective inhibitor, and TGX-221, a -selective inhibitor. FIG.2D demonstrates a bar graph measuring the difference in sensitivity between the PIK3CA GOF mutant and PIK3CA wildtype cell lines through a ratio of IC50concentrations.

[0013] FIGs. 3A-3D illustrate the activity of p110 inhibitors in cells with and without mutation in aPIK3CA gene (MDA-MB- -MB-453 cells: H1047R mutated). FIG.3A demonstrates the inhibition of MDA-MB-231 and MDA-MB-453 cells withWSGR Ref: 64162-710.601 mutant selective inhibitor inavolisib, alone. FIG. 3B demonstrates the inhibition ofMDA-MB-231 and MDA-MB-453 -selective inhibitor GSK-2636771 alone. FIG.3C demonstrates the inhibition of MDA-MB-231 and MDA-MB-453 cells when treated with combination inavolisib, a mutant selective inhibitor, and GSK-2636771, a -selective inhibitor. FIG.3D demonstrates a bar graph measuring the difference in sensitivity between the GOF mutant and wildtype cell lines through a ratio of IC50concentrations.

[0014] FIGs. 4A-4D illustrate the activity of p110 inhibitors in cells with and without mutation in aPIK3CA gene (MDA-MB-231 cells: ; MDA-MB-453 cells: H1047R mutated FIG.4A demonstrates the inhibition of MDA-MB-231 and MDA-MB-453 cells when treated mutant selective inhibitor STX-478, alone. FIG.4B demonstrates the inhibition of MDA-MB-231 and MDA-MB-453 cells when treated -selective inhibitor AZD-8186 alone. FIG.4C demonstrates the inhibition of MDA-MB-231 and MDA- MB-453 cells when treated with a combination of STX-478, a mutant selective inhibitor, and AZD-8186, a -selective inhibitor. FIG. 4D demonstrates a bar graphmeasuring the difference in sensitivity between the GOF mutant and wildtype cell lines through a ratio of IC50concentrations.

[0015] FIGs. 5A-5D illustrate the activity of p110 inhibitors in cells with and without mutation in aPIK3CA gene (MDA-MB-231 cells: ; T47D cells: ).FIG. 5A demonstrates the inhibition of MDA-MB- mutantselective inhibitor STX-478, alone. FIG.5B demonstrates the inhibition of MDA-MB-231 and MDA-MB-453 cells with when treated with AZD-8186, a - selective inhibitor, alone. FIG.5C demonstrates the inhibition of MDA-MB-231 and T47D cells when treated with a combination of STX-478, a mutant selective inhibitor, and AZD-8186, a p1 -selective inhibitor. FIG. 5D demonstrates the difference in sensitivitybetween the GOF mutant and wildtype cell lines through a ratio of IC50concentrations.

[0016] FIGs. 6A-6D illustrate the activity of p110 inhibitors in cells with and without mutation in aPIK3CA gene (MDA-MB-231 cells: ; MDA-MB-453 cells: H1047R mutated FIG.6A demonstrates the inhibition of MDA-MB-231 and MDA-MB-453 cells when treated with STX-478, a mutant selective inhibitor, alone. FIG.6B demonstrates the inhibition of MDA-MB-231 and MDA-MB-453 cells when treated with GSK-2636771, a-selective inhibitor, alone. FIG.6C demonstrates the inhibition of MDA-MB-231 and MDA-MB-453 cells when treated with a combination of STX-478, mutant selective inhibitor, and GSK-2636771, a -selective inhibitor. FIG.6D demonstrates a bar graph measuring the difference in sensitivity between the GOF mutant and wildtype cell lines through a ratio of IC50concentrations.WSGR Ref: 64162-710.601

[0017] FIGs. 7A-7D illustrate the activity of p110 inhibitors in cells with and without mutation in aPIK3CA gene (MDA-MB- MDA-MB-453 cells: H1047R mutated. FIG.7A demonstrates the inhibition of MDA-MB-231 and MDA-MB-453 cells when treated mutant selective inhibitor, RLY-2608, alone. FIG.7B demonstrates the inhibition of MDA-MB-231 and MDA-MB-453 cells when treated -selective inhibitor, TGX-221, alone. FIG.7C demonstrates the inhibition of MDA-MB-231 and MDA- MB-453 cells when treated with a combination of a mutant selective inhibitor, RLY- 2608, and a -selective inhibitor, TGX-221. FIG.7D demonstrates a bar graph measuring the difference in sensitivity between the GOF mutant and wildtype cell lines through a ratio of IC50concentrations.

[0018] FIGs. 8A-8B illustrate the activity of p110 inhibitors in cells with and without mutation in aPIK3CA gene (MDA-MB- MDA-MB-453 cells: H1047R mutated. FIG.8A demonstrates the inhibition of MDA-MB-231 and MDA-MB-453 cells when treated with a combination of a mutant selective inhibitor, STX-478, and 3- fold titrated concentration of a -selective inhibitor, AZD-8186. FIG.8B demonstrates the inhibition of MDA-MB-231 and MDA-MB-453 cells when treated with a combination of a 3-fold concentration of a mutant selective inhibitor, STX-478, and a low dose of a -selective inhibitor, AZD-8186.

[0019] FIG. 9 illustrate the activity of p110 inhibitors in cells with and without mutation in aPIK3CA gene (MDA-MB- MDA-MB-453 cells: H1047R mutated. The figure demonstrates the inhibition of MDA-MB-231 and MDA-MB-453 cells when treated with a combination of a low dose of a mutant selective inhibitor, STX- 478, and 3-fold titrated concentration of a -selective inhibitor, GSK-2636771.

[0020] FIGs. 10A-10D illustrate the activity of p110 inhibitors in cells with and without mutation ina PIK3CA gene (MDA-MB- MDA-MB-453 cells: H1047R mutated. FIG.10A demonstrates the inhibition of MDA-MB-231 and MDA-MB-453 cells when treated with a (non-mutant selective), alpelisib, alone. FIG.10B demonstrates the inhibition of MDA-MB-231 and MDA-MB-453 cells when treated with a -selective inhibitor, GSK-2636771, alone. FIG. 10C demonstrates the inhibition ofMDA-MB-231 and MDA-MB-453 cells when treated with a combination of ainhibitor (non-mutant selective), alpelisib, and a -selective inhibitor, GSK-2636771. FIG.10D demonstrates a bar graph measuring the difference in sensitivity between the GOF mutant and wildtype cell lines through a ratio of IC50concentrations.

[0021] FIGs. 11A-11D illustrate the activity of p110 inhibitors in cells with and without mutation ina PIK3CA gene (MDA-MB- MDA-MB-453 cells: H1047R mutatedWSGR Ref: 64162-710.601 . FIG.11A demonstrates the inhibition of MDA-MB-231 and MDA-MB-453 cells when treated with a (non-mutant selective), alpelisib, alone. FIG.11B demonstrates the inhibition of MDA-MB-231 and MDA-MB-453 cells treated with a - selective inhibitor, TGX-221, alone. FIG.11C demonstrates the inhibition of MDA-MB-231 and MDA-MB-453 cells treated with a combination of a (non-mutant selective), alpelisib, and a -selective inhibitor, TGX-221. FIG.11D demonstrates a bar graph measuring the difference in sensitivity between the GOF mutant and wildtype cell lines through a ratio of IC50concentrations.

[0022] FIGs. 12A-12D illustrate the effect of a mutant-selective PI3K alpha inhibitor, inavolisib, anda PI3K inhibitor, SAR260301, on DLD1 cells with and without a E545K PIK3CA gain offunction mutation.. FIG.12A shows the results of DLD1 cells + / - E545K mutation treated with inavolisib. FIG. 12B shows the results of DLD1 cells + / - E545K mutation treated withSAR260301. FIG.12C shows the results of DLD1 cells + / - E545K mutation treated with inavolisib and SAR260301. FIG.12D shows difference in IC50 between wildtype and mutant cells when treated with inavolisib alone, SAR260301 alone, and the combination of inavolisib and SAR260301.

[0023] FIGs. 12E-12H illustrate the effect of non-mutant selective inhibitor, alpelisib, and , and aPI3K inhibitor, SAR260301, on DLD1 cells with and without a E545K PIK3CA gain offunction mutation. FIG.12E shows the results of DLD1 cells + / - E545K mutation treated with alpelisib. FIG. 12F shows the results of DLD1 cells + / - E545K mutation treated withSAR260301. FIG.12G shows the results of DLD1 cells + / - E545K mutation treated with SAR26030 and alpelisib. FIG.12H shows difference in IC50 between wildtype and mutant cells when treated with alpelisib alone, SAR260301 alone, and the combination of alpelisib and SAR260301.

[0024] FIGs. 13A-13F illustrate the viability of three different cell lines after treatment with variouscombinations of inavolisib and SAR260301. FIGs.13A and 13B illustrate inhibition of SKOV3 - H1047R PIK3CA mutant ovarian cell line by treatment of inavolisib and SAR260301. FIGs.13C and 13D illustrate inhibition of MDA-MB-453 cells having H1047Rmutant breast cell line by treatment of inavolisib and SAR260301. FIGs. 13Eand 13F illustrate inhibition of MDA-MB-231 - WT PIK3CA breast cell line by treatment ofinavolisib and SAR260301.

[0025] FIG. 14A illustrates the results of mice injected with MDA-MB-453 cells having H1047Rtreated with a combination of inavolisib and GSK-2636771, inavolisib alone,GSK-2636771 alone, or vehicle. FIG. 14B illustrate the results of mice treated with thecombination of inavolisib and SAR260301, inavolisib alone, SAR260301 alone, or vehicle.WSGR Ref: 64162-710.601

[0026] FIGs. 15A-15D illustrate the activity of p110 inhibitors in cells with and without mutation ina PIK3CA gene (MDA-MB- -MB-453 cells: H1047R mutatedFIG.15A demonstrates the inhibition of MDA-MB-231 and MDA-MB-453 cells inavolisib, alone. FIG.15B demonstrates the inhibition of MDA-MB-231 and MDA-MB- -selectiveinhibitor AZD-6482 alone. FIG.15C demonstrates the inhibition of MDA-MB-231 and MDA-MB-453 cells when treated with a combination of a inavolisib selective inhibitor, and AZD-6482 -selective inhibitor. FIG. 15D demonstrates a bargraph measuring the difference in sensitivity between the PIK3CA GOF mutant and PIK3CA wildtype cell lines through a ratio of IC50concentrations.

[0027] FIG. 16 demonstrates the inhibition of HCC1954 cells (from a breast cancer cell line) with aPIK3CA GOF mutation after treatment with vehicle alone, inavolisib alone, GSK2636771 alone, or a combination of inavolisib and GSK2636771. DETAILED DESCRIPTION OF THE INVENTION

[0028] While various embodiments of the invention have been shown and described herein, it will beobvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions may occur to those sk illed in the artwithout departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed.

[0029] The present disclosure provides for new methods of treatment or prevention of cancers,resulting in unexpectedly superior cancer cell inhibition or cancer treatment. The methods provided herein may utilize combination therapy to overcome challenges associated with p110inhibitors, such as the development of resistance to p110 inhibitors, or insufficient efficacy. As commonly used in the literature and by those skilled in the art, the term PI3K inhibitors broadly refers to compounds that inhibit class I phosphoinositide 3-kinases, including isoform- inhibitors s are encompassed within the term PI3K inhibitors

[0030] In particular embodiments, the present disclosure provides new methods and kits for treating acancer through combination therapy. In some embodiments, the method comprises treating a cancer comprising a mutation in a PIK3CA gene. In some embodiments, the mutation is a gain of function mutation. In some embodiments, the gain of function mutation is in a PIK3CA gene. In some embodiments, the combination therapy comprises a and aWSGR Ref: 64162-710.601 inhibitor.

[0031] In some embodiments, the present disclosure provides methods of treating or reducing theincidence of a cancer, said method comprising administering said composition to a subject in need thereof, wherein said composition comprises two phosphoinositide 3- p110inhibitors. In some embodiments, the present disclosure provides methods of increasing tumor growth inhibition in a subject, said method comprising administering said composition to a subject in need thereof, wherein said composition comprises two phosphoinositide 3-kinase inhibitors. In some embodiments, said cancer or tumor has an increased amount, function, or signaling activity of (e.g., as compared to a wild-type amount, function, or signaling activity of ). In some embodiments, said cancer has been previously determined as comprising an increased amount, function, or signaling activity of as compared to a wild-type amount, function, or signaling activity of . The increased amount, function, or signaling activity of may be a result of a mutation causing orcaused by the cancer. In some embodiments, the treatment comprises a combination treatment. In some embodiments, the combination treatment comprises a -mutation selective -selective inhibitor. In some embodiments, the combination treatment works synergistically to inhibit a cancer containing an increased amount, function, or signaling activity of I. Methods of Treating Cancer

[0032] Provided herein, in some embodiments, are methods of treating a cancer in a patient in needthereof. In some embodiments, the method comprises administering (e.g., a therapeutically effective amount of) a composition, such as any of the compositions described herein, to a patient having a cancer. In some embodiments, the composition comprises a first p110 inhibitor and a second p110 inhibitor. In some embodiments, the first p110 inhibitor is a p110 inhibitor. In some embodiments, the first p110 inhibitor iIn some embodiments, the first embodiments, the second In some embodiments, the second is a selective inhibitor. In some embodiments, the composition comprises In some embodiments, the cancer comprises a mutation of a gene (e.g., PIK3CA gene). In some embodiments, the mutation is a gain of function mutation. In some embodiments, the cancer has been determined (e.g., previously determined) as comprising a gain of function mutation of a gene(e.g., PIK3CA gene). In some embodiments, said patient comprises an increased amount (i.e.,WSGR Ref: 64162-710.601 number), function, or signaling activity of . In some embodiments, said increased amount, function, or signaling activity of is in a cancer cell of the subject.

[0033] In some embodiments, the is administered once a day. In some embodiments,the is administered twice a day. In some embodiments, the is administered twice a day and the inhibitor (e.g., inhibitor) is administered once a day. a. p110 Inhibitors

[0034] Phosphoinositide 3-kinase (PI3K) signaling may be involved in important physiological andpathophysiological functions that drive tumor progression, such as metabolism, cell growth, proliferation, angiogenesis and metastasis. Pharmacological or genetic suppression of this signaling may yield cancer cell death or regression of tumor growth. The PI3K pathway may be activated via point mutation of the PIK3CA gene or inactivation of the phosphatase and tensin homolog (PTEN) gene. Activation of this pathway occurs in approximately 30 50%human cancers and may contribute to resistance to various anti-cancer therapies.

[0035] PI3K proteins may be classified into three main classes (I, II and III) based on the substratespecificities and structural characteristics. Class I PI3Ks may be further categorized into two subtypes (A and B) based on the mode of regulation. Class IA PI3Ks form dimers comprising Class I PI3Ks may act downstream of both G protein-coupled receptors (GPCRs) and receptor tyrosine kinases (RTKs). In addition, these regulatory subunits may play an important role in stabilization of the p110 catalytic subunits and in suppression of the basal lipid kinase activity. Class IB PI3Ks, which may be activated downstream of GPCRs, may form heterodimers p84. Class IB PI3Ks consist of three isoforms (p110- p110-C2ß and p110-isoforms may have a RAS-binding domain (RBD), a helical domain, and a catalytic domain but may lack a regulatory domain. The class III PI3Ks, also known as vacuolar protein sorting 34 (VPS34), may heterodimerize with membrane-associated VPS15 regulatory subunit. This VPS34-VPS15 complex may be ubiquitously expressed in mammals regulating several functions such as phagocytosis, autophagy, endocytosis and intracellular trafficking. Some reports have considered mTOR as class IV PI3K-related kinases, whose catalytic domain isassociated with ataxia-telangiectasia (ATM), fluorescence recovery after photo bleaching (FRAP) and transformation / transcription domain-associated protein (TRRAP) and FK506- binding protein 12 (FKBP12) / rapamycin (FRB)-binding domain and a C-terminal FAT domain (FATC). There are two Huntington elongation factor 3, PR65 / A subunit of protein phosphatase 2A, TOR (HEAT) repeats in the N-terminal region which modulate the proteinWSGR Ref: 64162-710.601 protein interactions in mTOR signaling. The four described isoforms of the catalytic subunit PIK3CA, PIK3CB, PIK3CG, and PIK3CD, respectively.

[0036] Inhibiting compounds (e.g., small-molecule inhibitors) targeting p110 include pan, isoform-selective, and dual p110 / mTOR inhibitors. To date, a number of p110 inhibitors have been approved by the United States Food and Drug Administration (FDA). However, other p110 inhibitors are actively being researched. Provided below are non-limiting descriptions of a few exemplary p110 inhibitors. b. i. Alpelisib

[0037] Alpelisib is indicated, in combination with fulvestrant, for the treatment of postmenopausal women, and men, with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, PIK3CA mutated, advanced or metastatic breast cancer as detected by an FDA-approved test following progression on or after an endocrine-based regimen. It showed IC50 of 5 nM in a cell- fect on

[0038] -subunit of p110(PIK3CA -signaling, cellular transformation and thegeneration of tumors in in vitro and in vivo models. In breast cancer cell lines, alpelisib inhibited the phosphorylation of p110 downstream targets, including Akt, and showed activity in cell lines harboring a PIK3CA mutation. In vivo, alpelisib inhibited the p110 / Akt signaling pathway and reduced tumor growth in xenograft models, including models of breast cancer. p110 inhibition by alpelisib treatment has been shown to induce an increase in estrogen receptor (ER) transcription in breast cancer cells. The combination of alpelisib and fulvestrant demonstrated increased antitumor activity compared to either treatment alone in xenograft models derived from ER-positive, PIK3CA mutated breast cancer cell lines.AlpelisibWSGR Ref: 64162-710.601 ii. STX-478

[0039] STX-478 is a potent and mutant selective Specifically, STX-478 has. STX-478 has been reported to have IC50values as low as 9.4 nM for H1047R mutant , and has shown to have approximatelygreater than 14-fold selectivity over the wildtype . Additionally, STX-478 has been shown to be brain penetrant.STX-478 iii. RLY-2608

[0040] RLY-2608 is a potent and mutant selective -2608 has. STX-478 has been reported to have IC50values as low as 334 nM for H1047R mutant , and has shown to have approximatelygreater than 2-fold selectivity over the wildtype .RLY-2608 iv. LOXO-783

[0041] LOXO-783 is a potent and mutant selective -783 has. LOXO-783 has been reported to have IC50values as low as 4 nM for H1047R mutant , and has shown to have approximatelygreater than 75-fold selectivity over the wildtype . Additionally, LOXO-783 has been shown to be brain penetrant.WSGR Ref: 64162-710.601 v. SNV-4818

[0042] SNV-4818 is a potent and mutant selective -4818 has. vi. Inavolisib

[0043] Inavolisib is a potent and mutant selective inavolisib has. Inavolisib has been reported to have IC50 values aslow as 0.04 nM for , and has shown to have up to 300-fold selectivity over the other inavolisib has been shown to be aand has been shown to preferentially degrade and functionally inhibit E542K, E545K, andH1047R mutant forms of .Inavolisib vii. Copanlisib

[0044] Copanlisib has been indicated for the treatment of adult patients with relapsed follicularlymphoma (FL) who have received at least two prior systemic therapies. Copanlisib is an inhibitor of phosphatidylinositol-3-kinase (p110) with inhibitory activity predominantly IC50of 0.5, 3.7, 6.4, and 0.7 nM in cell- Copanlisib has beenshown to induce tumor cell death by apoptosis and inhibition of proliferation of primary malignant B cell lines. Copanlisib has been shown to inhibit several key cell-signaling pathways, including B cell receptor (BCR) signaling, CXCR12 mediated chemotaxis of ell lines.CopanlisibWSGR Ref: 64162-710.601 viii. RLY-5836

[0045] RLY-5836 is a mutant selective . Upon oral administration, RLY-5836selectively targeted and allosterically bound to PIK3CA mutated forms, thereby preventing the activity of PIK3CA mutants. This prevented mutant PIK3CA-mediated activation of the PI3K / Akt (protein kinase B) / mammalian target of rapamycin (mTOR) pathway. This resulted in both apoptosis and growth inhibition in PIK3CA mutant-expressing tumor cells.

[0046] Exemplary mutant selective s may be found in U.S. patent application number17 / 921,580 Pi3k-alpha inhibitors and methods of use thereof US20240287058A1), which was filed on April 29, 2024 and is incorporated by reference herein in its entirety. ix. LY4045004

[0047] LY4045004 is a mutant selective . LY4045004 demonstrated tumorregressions in ER+,HER2- -mutant breast cancer models withoutcausing significant weight loss or increase in insulin or C-peptide. i. BPI-21668

[0048] BPI-21668is a mutant selective inhibitor. Upon oral administration, BPI-21668selectively targeted, bound to, and inhibited the activity of PIK3CA mutant(s) in the PI3K / Akt (protein kinase B) / mammalian target of rapamycin (mTOR) pathway. This resulted in both apoptosis and growth inhibition in PIK3CA mutant-expressing tumor cells. c. i. GSK-2636771

[0049] GSK-2636771 (CAS No. 1372540-25-4) is a substituted benzimidazole and is a potent,selective and orally bioavailable inhibitor of class I . t has demonstratedan IC50of 5.2 nM, a 900-fold selectivity over -fold selectivity over GSK-2636771 in Subjects With Advanced Solid Tumors With Phosphatase and Tensin was underway to identify the effects of GSK-2636771 inpatients whose cancer has a complete loss of PTEN expression.WSGR Ref: 64162-710.601GSK-2636771

[0050] Provided herein, in some embodiments, is a method of treating a cancer in a patient in needthereof, said method comprising administering GSK- inhibitor, wherein said cancer has a mutation of a PIK3CA gene. In some embodiments, the mutation is a gain of function mutation. In some embodiments, said cancer has been previously determined as comprising a gain of function mutation of a PIK3CA gene. Furtherprovided herein in some embodiments, is a method of treating a cancer in a patient in need thereof, said method comprising administering GSK- inhibitor, wherein said patient has an increased amount, function, or signaling activity of -type amount, function, or signaling activity some embodiments, said cancer has been previously determined as comprising an increased amount, function, or signaling activity -type amount, function, or signaling activity

[0051] Provided herein, in some embodiments, is a method of treating a cancer in a patient in needthereof, said method comprising administering GSK-2636771 inhibitor, wherein said cancer has a mutation of a PIK3CA gene. In some embodiments, the mutation is a gain of function mutation. In some embodiments, said cancer has been previously determined as comprising a gain of function mutation of a PIK3CA gene. Further provided herein in some embodiments, is a method of treating a cancer in a patient in need thereof, said method comprising administering GSK-2636771 inhibitor, wherein said patient has an increased amount, function, or signaling activity of (e.g., as compared to a wild-type amount, function, or signaling activity of ). In some embodiments, said cancer has been previously determined as comprising an increased amount, function, or signaling activity of (e.g., as compared to a wild-type amount, function, or signaling activity of ).

[0052] For more information on GSK-2636771, see: Preparation of benzimidazole derivatives as PI3kinase inhibitors, Qu, et.al., WO2012047538 A12012-04-12; and A First-Time-in-Human Study of GSK-2636771, a Phosphoinositide 3 Kinase Beta-Selective Inhibitor, in PatientsWSGR Ref: 64162-710.601 with Advanced Solid Tumors By: Mateo, Joaquin; Ganji, Gopinath; Lemech, Charlotte; Burris, Howard A.; Han, Sae-Won; Swales, Karen; Decordova, Shaun; De Young, M. Phillip; Smith, Deborah A.; Kalyana-Sundaram, Shanker; et al Clinical Cancer Research (2017), 23(19), 5981-5992, which are herein by reference in their entirety.ii. AZD-8186

[0053] AZD-8186 is a p110 inhibitor, which has demonstrated potent inhibition of and p110 .AZD-8186 has demonstrated an IC50 of 4 nM, 12 nM, 35 nM, and 675 nM, for p110 , p110 ,and p110 , respectively. In a broad panel of protein and lipid kinase assays, selectivityfor p110 p100 - -8186demonstrated no significant binding to 442 other kinases in a KinomeScan screen. AZD-8186 showed selectivity for p110 family kinases and no other off -target activity was detected. In aPTEN-null line, in MDA-MB-468 cells, AZD-8186 inhibited p110 -dependent activation ofpAKT (Ser473) with an IC50value of 3 nM. Potency in the PIK3CA-mutant line BT474c was 752 nM, which demonstrated selectivity for p110 . IgM mediated stimulation ofB cells resulted in phosphorylation of AKT through activation of p110 -8186 inhibitedIgM-stimulated phosphorylation of pAKT (Ser473) activation in JEKO cells with an IC50value of 17 nM. In cell proliferation assays, AZD-8186 inhibited proliferation of MDA- MB-468 cells with a GI50value of 65 nM (compared to IgM stimulated JEKO cell growth with an IC50value of 228 nM). It only inhibited BT474c cell growth with an IC50value of AZD-8186 s selectivity for p110 .AZD-8186

[0054] To assess single-agent efficacy of AZD-8186 in vivo, antitumor activity has been assessed inthe PTEN-null TNBC models HCC70 and MDA-MB-468, and the prostate models PC3 and HID28. At 25 and 50 mg / kg twice a day, AZD-8186 was shown to inhibit the growth of all four models. At 25 and 50 mg / kg, HCC70 was inhibited at 62% (P<0.001) and 85% (P<0.001), respectively, MDA-MB-468 was inhibited at 47% (P<0.001) and 76% (P<0.001), respectively, at end at of this study, with regression early in the study. Efficacy in the PTEN- null prostate model, PC3 was less pronounced with 25 and 50 mg / kg giving maximal growthWSGR Ref: 64162-710.601 inhibition of 59% (P<0.001) and 64% (P<0.001), respectively. In contrast, AZD-8186 gave 79% (P<0.001) growth inhibition in the PTEN-null prostate explant model HID28. In mouse, AZD-8186 demonstrated a short half -life delivering a PK profile that resulted in intermittentcover over 24 hours dosing interval. To increase the time of exposure, animals bearing PC3 tumors were co-dosed with AZD-8186 in the presence of the Cyt P450 inhibitor ABT, which resulted in significantly increased exposure. This was also shown to increase the efficacy in the PC3 model with 86% (P<0.005) reduction in tumor growth achieved with 30 mg / kg AZD- 8186+ABT.

[0055] Provided herein, in some embodiments, is a method of treating a cancer in a patient in needthereof, said method comprising administering AZD- inhibitor, wherein said cancer has a mutation of a PIK3CA gene. In some embodiments, the mutation is a gain of function mutation. In some embodiments, said cancer has been previously determined as comprising a gain of function mutation of a PIK3CA gene. Further provided herein in some embodiments, is a method of treating a cancer in a patient in need thereof, said method comprising administering AZD- inhibitor, wherein said patient has an increased amount, function, or signaling activity of -type amount, function, or signaling activity some embodiments, said cancer has been previously determined as comprising an increased amount, function, or signaling activity -type amount, function, or signaling activity

[0056] For more information on AZD-8186, see: Chromenone derivatives, Barlaam, et. al. US8,399,460; and Discovery of (R)-8-(1-(3,5-Difluorophenylamino)ethyl)-N,N-dimethyl-2- morpholino-4-oxo-4H-chromene-6-carboxamide (AZD-8186): A Potent and Selective Inhibitor of p110 p110 -Deficient Cancers By: Barlaam, er.al. Journal of Medicinal Chemistry (2015), 58(2), 943-962, which are herein by reference in their entirety. iii. AZD-6482

[0057] AZD-6482 (KIN-193, TBO-309) is a potent and selective p110 . Specifically, AZD-6482 is a that has demonstrated an IC50 of 0.69 nM. In an in vitro kinaseassay AZD-6482 has demonstrated 200, 20, and 70-fold selectivity for over , -6482 may also exhibit selectivity of ~80-fold over p110- -PK and more than 1,000-fold over other phosphatidylinositol-3kinase related kinases (PIKKs). An inhibitor-kinase interaction profiling of AZD-6482against a panel of 433 kinases using the KinomeScan approach demonstrated that AZD-6482WSGR Ref: 64162-710.601 is highly selective in its interaction with p110s. AZD-6482 may selectively target PTEN- deficient tumors. When AZD-6482 was tested on cell proliferation on a large panel of 422 cancer cell lines using high-throughput tumor cell line profiling, 35% of cell lines with PTEN mutations (20 out of 57) and 16% of cell lines with wild-type PTEN (58 out of 365) were sensitive to AZD-6482 with a threshold of EC50<5 µM.AZD-6482

[0058] Provided herein, in some embodiments, is a method of treating a cancer in a patient in needthereof, said method comprising administering AZD-6482 inhibitor, wherein said cancer has a mutation of a PIK3CA gene. In some embodiments, the mutation is a gain of function mutation. In some embodiments, said cancer has been previously determined as comprising a gain of function mutation of a PIK3CA gene. Further provided herein in some embodiments, is a method of treating a cancer in a patient in need thereof, said method comprising administering AZD-6482 inhibitor, wherein said patient has an increased amount, function, or signaling activity of -type amount, function, or signaling activity some embodiments, said cancer has been previously determined as comprising an increased amount, function, or signaling activity -type amount, function, or signaling activity iv. SAR-260301

[0059] SAR-260301 is an orally available and selective p110 inhibitor. It has demonstrated an IC50of 1539, 23, 469, and 10000 nM against p110 , p110 , p110 , and p110 SAR-260301 has shown promising preclinical activity against a range of cancer types, includingbreast, prostate, and ovarian cancers. It has been shown to inhibit p110 downstream pathways, leading to cell death in cancer cells. SAR-260301 was evaluated in clinical trials for the treatment of advanced solid tumors, with a focus on breast and prostate cancers.WSGR Ref: 64162-710.601SAR-260301 v. KA-2237

[0060] KA-2237 is an oral, potent, dual p110 p110 ) inhibitor. In preclinicalstudies, KA- - -dependent AKT activation and suppressedproliferation of diverse hematological and epithelial tumors. vi. Idelalisib

[0061] Idelalisib is an inhibitor of phosphatidylinositol 3-kinase delta ( ), which may beexpressed in normal and malignant B cells. It showed an IC50of 2.5 nM in cell-free assays for ,where the selectivity for p110 was 40- to 300-fold greater thanhas been shown to induce apoptosis and inhibit proliferation in cell lines derived from malignant B cells and in primary tumor cells. Idelalisib also inhibited several cell signaling pathways, including B cell receptor (BCR) signaling and CXCR4 and CXCR5 signaling, which are involved in trafficking and homing of B cells to the lymph nodes and bone marrow. Treatment of lymphoma cells with idelalisib has been shown to inhibit chemotaxis and adhesion, and reduce cell viability.Idelalisib vii. Duvelisib

[0062] Duvelisib is indicated for the treatment of adult patients with relapsed or refractory chroniclymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) after at least two prior therapies. Duvelisib is an inhibitor of p110 with inhibitory activity predominantly againstand isoforms, which may be abnormally expressed in normal and malignant B cells. Duvelisib demonstrated an IC50of 1 nM for and 50 nM for in cell-freeWSGR Ref: 64162-710.601 assays. Duvelisib has been shown to induce growth inhibition and reduce viability in cell lines derived from malignant B cells and in primary CLL tumor cells. Duvelisib was shown toinhibit several key cell-signaling pathways, including B cell receptor signaling and CXCR12- mediated chemotaxis of malignant B cells. Additionally, duvelisib inhibited CXCL12-induced T cell migration and M-CSF and IL-4 driven M2 polarization of macrophages.Duvelisib viii. Seletalisib

[0063] Seletalisib (UCB5857) is potent and selective p110 IC50 of 12 nM forp110 seletalisib has been shown to block AKT phosphorylation followingactivation of the BCR in a B cell line. Seletalisib inhibited N-formyl peptides (fMLP)- stimulated, but not phorbol myristate acetate (PMA)-stimulated superoxide release from human neutrophils consistent with a p110 -selective activity. No indications of cytotoxicitywere observed in PBMCs or other cell types treated with seletalisib. Seletalisib was shown to block human T cell production of several cytokines from activated T cells. Seletalisib was also shown to inhibit T cell differentiation to Th1, Th2, and Th17 subtypes. Additionally, seletalisib inhibited B cell proliferation and cytokine release. In human whole blood assays, seletalisib inhibited CD69 expression upon B cell activation and anti-IgE-mediated basophildegranulation.Seletalisib

[0064] For more information on seletalisib, see: WO2012032334 A1 2012-03-15; and EuropeanJournal of Clinical Pharmacology (2017), 73(5), 581-591, which are herein by reference in their entirety.WSGR Ref: 64162-710.601 ix. Acalisib

[0065] Acalisib (GS-9820) is a potent and selective p110 inhibitor. Acalisib has been reported tohave IC50 values as low as 12.7 and 14 nM against p110 , and has shown to haveapproximately greater than 100-fold selectivity over the other class I p110 enzymes. Acalisibhas demonstrated an IC50 of 3377 against p110 It is suggested that acalisib may not haveactivity against Class II and III p110 family members.Acalisib (GS-9820) x. TGX-221

[0066] TGX-221 is a potent and selective p110 . Specifically, TGX-221 has demonstratedactivity as . TGX-221 has been reported to have IC50 values as low as 5 nMfor p110 , and has shown to have between 35-1000-fold selectivity over the other p110enzymes (e.g., ). Additionally, TGX-221 has been shown to have high cell permeability.TGX-221 xi. PIK-108

[0067] PIK-108 is a -108 has. PIK-108 has been reported to have IC50values as low as 57 n 45-fold selectivity over theWSGR Ref: 64162-710.601PIK-108 d.

[0068] In some embodiments, the methods provided herein comprise administering a mutant selective- 478, RLY-2608, LOXO-783, SNV-4818, inavolisib, or a combination thereof. The p110 In some embodiments, the methods provided econd p110 inhibitor.

[0069] second p110 inhibitor. In some embodiments, the second p110 inhibitor comprises a p110inhibitor of som -478. In some-2608. In some -783. In some -4818. In some embodime inavolisib.

[0070] (I):Formula (I), or a pharmaceutically acceptable salt thereof, wherein:WSGR Ref: 64162-710.601 Z is O or NRx; Rxis hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl; each R1is independently selected from halogen, hydroxyl, cyano, C1-C6 alkyl optionally substituted with hydroxyl, and C3-C6 cycloalkyl; m is 0, 1, 2, or 3; R2is halogen, hydroxyl, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 haloalkyl, C3-C6 cycloalkyl optionally substituted with 1 or 2 fluoro; R3is a C1-C6 alkyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with 1 or 2 substituents independently selected from fluoro and C1-C6 alkyl; Ring A is a 6-10 membered aryl, a C3-C8 cycloalkyl, a 5-10 membered heteroaryl, or a 4-10 membered heterocyclyl; each R4is independently selected from the group consisting of: (i) halogen, (ii) C1-C6 alkyl optionally substituted with 1 or 2 hydroxyl or NRARB, (iii) C1-C6 alkoxy optionally substituted with 1-2 substituents independently selected from hydroxyl and C3-C6 cycloalkyl, (iv) C1-C6 haloalkyl, (v) hydroxyl, (vi) cyano, (vii) CO2H, (viii) NRARB, A2, (x)CRD, (xi) SO2(NRERF), (xii) SO2(C1-C6 alkyl), (xiii) -C6 alkyl), (xiv) -C6 alkyl), (xv) CO2(C1-C6 alkyl), (xvi) 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl, (xvii) 3-9 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG, and (xviii) 3-6 membered cycloalkyl optionally substituted with 1 or 2 independently selected RG; n is 0, 1, or 2; each RA, RA1, RB, RB1, RC, RC1, RD, RD1, RE, and RFis independently (i) hydrogen,WSGR Ref: 64162-710.601 (ii) hydroxyl, (iii) 4-6 membered heterocyclyl, (iv) C1-C6 haloalkyl, (v) -C6 alkyl), (vi) -C6 alkyl), (vii) SO2(C1-C6 alkyl), (viii) 3-6 membered cycloalkyl optionally substituted with hydroxyl, or (ix) C1-C6 alkyl optionally substituted with 1-2 substituents independently selected from hydroxyl,B2RC2, 5-6 membered heteroaryl, 3-6 membered cycloalkyl, SO2(C1- C6 alkyl), CO2H, and SO2(NH2); or RCand RD, together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from hydroxyl, halogen,B1RC1, SO2(C1-C6 alkyl), CO2H, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 alkoxy, and C1-C6 haloalkoxy; each RA2, RB2, and RC2is independently hydrogen or C1-C6 alkyl; each RGis independently selected from the group consisting of: fluoro, cyano, hydroxyl, C1- C6 alkyl optionally substituted with hydroxyl, C1-C6 alkoxy, NRA1RB1 A2, C1RD1, CO2(C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 haloalkoxy, SO2(C1-C6 alkyl), and CO2H.

[0071] to Formula (II):Formula (II), or a pharmaceutically acceptable salt thereof, wherein: Eis C(O) , C(RE)2 , C(RE)2C(RE)2 , C(S) , S(O)2 , OC(O) ,N(RE)C(O) , C(O)N(RE) , or C(RE)2C(O) ;Q is CH, C(RQ), or N; X is CH, C(RX), or N; Y is CH, C(RY), or N; Z is CH, C(RZ), or N; R1is -L1-R1A; R2is -L2-R2A; each instance of REis independently H or -LE-REA.WSGR Ref: 64162-710.601 RQis -LQ-RQA; RXis -LX-RXA; RYis -LY-RYA; RZis -LZ-RZA; or two instances of REare taken together with their intervening atoms to form a 3-8 membered saturated or partially unsaturated monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8-12 membered saturated or partially unsaturated bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein each ring is substituted with n instances of REEC; RQand R1are taken together with their intervening atoms to form a 4-8 membered saturated or partially unsaturated monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8-12 membered saturated or partially unsaturated bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein each ring is substituted with p instances of RQ1C; RYand RZare taken together with their intervening atoms to form a 4-7 membered partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said ring is substituted with q instances of RYZC; each of L1, L2, LE, LQ, LX, LY, and LZis independently a covalent bond, or a C1-4bivalent saturated or unsaturated, straight or branched hydrocarbon chain wherein one or twomethylene units of the chain are optionally and independently replaced by CH(RL) ,C(RL)2 , C3-6 cycloalkylene, C3-6 heterocycloalkylene, N(R) , N(R)C(O) ,N(R)C(NR) , N(R)C(NOR) , N(R)C(NCN) , C(O)N(R) , N(R)S(O)2 ,S(O)2N(R) , O , C(O) , OC(O) , C(O)O , S , S(O) , or S(O)2 ;R1Ais RAor RBsubstituted by r1instances of R1C; R2Ais RAor RBsubstituted by r2instances of R2C; REAis RAor RBsubstituted by r3instances of REC; RQAis RAor RBsubstituted by r4instances of RQC; RXAis RAor RBsubstituted by instances of RXC; RYAis RAor RBsubstituted by r6instances of RVC; RZAis RAor RBsubstituted by r7instances of RZC; RLis RAor RBsubstituted by r8instances of RLC; each instance of RAis independently oxo, deuterium, halogen, CN, NO2, OR, SF5, SR, NR2, S(O)2R, S(O)2NR2, S(O)2F, S(O)R, S(O)NR2, S(O)(NR)R, C(O)R, C(O)OR, C(O)NR2, C(O)N(R)OR, OC(O)R, OC(O)NR2,WSGR Ref: 64162-710.601 N(R)C(O)OR, N(R)C(O)R, N(R)C(O)NR2, N(R)C(NR)NR2, N(R)S(O)2NR2, N(R)S(O)2R, P(O)R2, P(O)(R)OR, or B(OR)2; each instance of RBis independently a C1-6aliphatic chain; phenyl; naphthyl; cubanyl; adamantyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each instance of R1C, R2C, REC, RQC, RXC, RYC, RZC, RLC, REEC, RQ1C, and RYZCis independently oxo, deuterium, halogen, CN, NO2, OR, SF5, SR, NR2, S(O)2R, S(O)2NR2, S(O)2F, S(O)R, S(O)NR2, S(O)(NR)R, C(O)R, C(O)OR, C(O)NR2, C(O)N(R)OR, OC(O)R, OC(O)NR2, N(R)C(O)OR, N(R)C(O)R, N(R)C(O)NR2, N(R)C(NR)NR2, N(R)S(O)2NR2, N(R)S(O)2R, P(O)R2, P(O)(R)OR, B(OR)2, or an optionally substituted group selected from C1-6aliphatic, phenyl, a3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 -2heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each instance of R is independently hydrogen, or an optionally substituted group selected from C1-6aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two R groups on the same nitrogen are taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur; andeach of n, p, q, r1, r2, r3, r4, r5, r6, r7, and r8is independently 0, 1, 2, 3, or 4.

[0072] to Formula (IIIa):WSGR Ref: 64162-710.601Formula (IIIa), or pharmaceutically acceptable salts thereof, wherein: R1is a group of the formula:R is H or C1-C3alkyl; R2is an optionally substituted bicyclic ring selected from 1,3-benzodioxole, 2,3-dihydro-1,4- benzodioxine, isoindolin-1-one, indolin-2-one, benzo[d]oxazol-2(3H)-one, 1,3-dihydro-2H- pyrrolo[2,3-b]pyridin-2-one, or 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine, or an optionally substituted bicyclic heteroaryl of 8 to 10 ring atoms containing 1, 2, 3, 4, or 5 ringWSGR Ref: 64162-710.601 heteroatoms independently selected from N, O, or S; wherein the optionally substituted bicyclic ring is optionally substituted with one to three substituents each independently selected from halogen and C1-C6alkyl; the optionally substituted bicyclic heteroaryl is optionally substituted with one to three substituents each independently selected from CN, halogen, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, SO2R10, C(O)OC1-C3alkyl, CONR10R10, NR10R10, NR10CO2R10, OH, an optionally substituted C1-C6alkyl, an optionally substituted C2-C6alkenyl, an optionally substituted C2-C6alkynyl, an optionally substituted C3-C5cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, an optionally substituted 1,3-benzodioxole, an optionally substituted 2,3-dihydro-1,4-benzodioxine, or an optionally substituted heteroaryl selected from pyridine, pyrimidine, pyridazine, pyrazine, pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optionally substituted C1-C6alkyl, C2-C6alkenyl, or C2-C6alkynyl is each optionally substituted with a CN, OH, oxetanyl, C1-C3alkoxy, CONR10R10, or phenyl; the optionally substituted C3- C5cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocycle or heteroaryl is each optionally substituted with one to three substituents each independently selected from halogen, C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, SO2R10, NR10R10, OH or CN; R3is H, halogen, CN, N(H)(C1-C3alkyl), N(C1-C3alkyl)2, N(H)(CH2CH2CO2H), C(O)C1-C3alkyl, C1-C6alkyl C1-C6haloalkyl, C1-C6hydroxyalkyl, C3-C5cycloalkyl, an optionally substituted heterocycle of 3 to 5 ring atoms containing 1, 2, or 3 ring heteroatoms independently selected from N, O, or S, or an optionally substituted heteroaryl of 5 or 6 ring atoms containing 1, 2, or 3 ring heteroatoms independently selected from N, O, or S; wherein the optionally substituted heterocycle or heteroaryl is each optionally substituted with one to three substituents each independently selected from halogen, C1-C3alkyl, or C1-C3haloalkyl; each of R4, R5and R6is independently H, halogen, C1-C6alkyl or C1-C6haloalkyl; R7is CN, C1-C6alkyl or C1-C6haloalkyl; R8is H or C1-C6alkyl; each R9is independently H, halogen, CN, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy or C3-C5cycloalkyl; and each R10is independently H or C1-C3alkyl.

[0073] to Formula (IIIb):WSGR Ref: 64162-710.601Formula (IIIb), or pharmaceutically acceptable salts thereof, wherein: R is H or C1-C3alkyl; R1is a group of the formula:R2is a group of the formula:WSGR Ref: 64162-710.601R3is H, halogen, CN, N(H)(C1-C3alkyl), N(C1-C3alkyl)2, N(H)(CH2CH2CO2H), C(O)C1-C3alkyl, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C3-C5cycloalkyl, an optionally substituted heterocycle of 3 to 5 ring atoms containing 1, 2, or 3 ring heteroatoms independently selected from N, O, or S, or an optionally substituted heteroaryl of 5 or 6 ring atoms containing 1, 2, or 3 ring heteroatoms independently selected from N, O, or S; wherein the optionally substituted heterocycle or heteroaryl is each optionally substituted with one to three substituents each independently selected from halogen, C1-C3alkyl, or C1-C3haloalkyl; each of R4, R5and R6is independently H, halogen, C1-C6alkyl or C1-C6haloalkyl; R7is CN, C1-C6alkyl or C1-C6haloalkyl; R8is H or C1-C6alkyl; each R9is independently H, halogen, CN, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, or C3-C5cycloalkyl; each R10is independently H, CN, halogen, C1-C6haloalkyl, C1-C6alkoxy, C1- C6haloalkoxy, SO2R11, C(O)OC1-C3alkyl, CONR11R11, NR11R11, NR11CO2R11, OH, an optionally substituted C1-C6alkyl, an optionally substituted C2-C6alkenyl, an optionally substituted C2-C6alkynyl, an optionally substituted C3-C5cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, an optionally substituted 1,3-benzodioxole, an optionally substituted 2,3-dihydro-1,4-benzodioxine, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optionally substituted C1-C6alkyl, C2-C6alkenyl, or C2-C6alkynyl is each optionally substituted with a CN, OH, oxetanyl, C1-C3alkoxy, or CONR11R11; the optionally substituted C3- C5cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocycle or heteroaryl is each optionally substituted with one to three substituents each independently selected from halogen, C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, SO2R11, NR11R11, OH or CN; and each R11is independently H or C1-C3alkyl.

[0074] to Formula (IIIc):WSGR Ref: 64162-710.601or pharmaceutically acceptable salts thereof, wherein:X is NR12 or O ;Y is C(R11)2 , O , NR11 , or S ;W is N , O , or S , wherein when W is O or S , R1 or R2 is absent;each R1and R2is independently H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, (CH2)mR12, (CH2)mOR12, (CH2)mN(R12)2, (CH2)mC(O)R12, (CH2)mC(O)OR12, (CH2)mC(O)N(R12)2, C3-C10cycloalkyl, heterocycle, aryl, or heteroaryl, wherein the cycloalkyl, heterocycle, aryl, and heteroaryl are optionally substituted 12, halogen, CN, NO2, C1-C6alkyl, C2-C6alkenyl, C2- C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, (CH2)nOR12, (CH2)nN(R12)2, (CH2)nC(O)R12, (CH2)nC(O)OR12, (CH2)nC(O)N(R12)2, (CH2)nSO2R12, C3- C6cycloalkyl, aryl, heteroaryl, or R15; or R1and R2, together with the nitrogen to which they are attached, form a heterocycle comprising 1-4 heteroatoms selected from O, N, and S, wherein the heterocycle is optionally substituted with one or more R10; each R3, R4, R5, and R6is independently H, halogen, CN, C1-C6alkyl, C2-C6alkenyl, C2- C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, (CH2)mR12, (CH2)mOR12, (CH2)mN(R12)2, (CH2)mC(O)R12, (CH2)mC(O)OR12, (CH2)mC(O)N(R12)2, C3- C10cycloalkyl, aryl, heterocycle comprising 1-4 heteroatoms selected from O, N, and S, or heteroaryl comprising 1-4 heteroatoms selected from O, N, and S; each R7and R8is independently H, halogen, CN, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxy; R9 11, halogen, CN, NO2, C1-C6alkyl, C2- C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, (CH2)mN(R12)2, (CH2)mOR12, (CH2)m CR13(OH) R12, (CH2)m C(O)R12, (CH2)m C(O)OR12, (CH2)mC(O)N(R12)2, (CH2)mC(O)N(OH)R12, (CH2)mSO2R12, (CH2)mSO2OR12, (CH2)mSO2N(R12)2, (CH2)mP(O)(OR12)2, (CH2)mP(O)(R12)2, (CH2)mP(O)(OR13)R12, (CH2)m B(OH)2, (CH2)m B(R12)2, (CH2)m O (CH2CH2 O)rR13,WSGR Ref: 64162-710.601 (CH2)m NR12 (CH2CH2 O)rR13, (CH2)m C(O) (CH2CH2 O)rR13, (CH2)mC(O)O (CH2CH2 O)rR13, (CH2)m C(O)NR12 (CH2CH2 O)rR13, (CH2)m C(O)NR12 SO2R13, (CH2)m SO2NR12 C(O)R13, (CH2)m S(O)(NR12) R13, C3-C10cycloalkyl, aryl, heterocycle comprising 1-4 heteroatoms selected from O, N, and S, or heteroaryl comprising 1-4 heteroatoms selected from N, O, and S, wherein the C1-C6alkyl, C2- C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C3-C10cycloalkyl, aryl, heterocycle, or heteroaryl is optionally substituted with one or more oxo, halogen, CN, OH, NH2, NO2, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxy, or two R9, together with the atoms to which they are attached form a C3-C10cycloalkyl, an aryl, or a heterocycle comprising 1-4 heteroatoms selected from O, N, and S, wherein the cycloalkyl, aryl, or heterocycle is optionally substituted with one or more oxo, halogen, CN, OH, NH2NO2, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1- C6alkoxy; R10at each occurrence is independently oxo, halogen, CN, C1-C6alkyl, C2-C6alkenyl, C2- C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, (CH2)nOR12, (CH2)nN(R12)2, (CH2)nC(O)R12, (CH2)nC(O)OR12, (CH2)nC(O)N(R12)2, (CH2)nSO2R12, (CH2)nO (CH2CH2 O)rR13, C3-C10 cycloalkyl, heterocycle, (CH2)n-aryl, or heteroaryl, whereinthe cycloalkyl, heterocycle, aryl, and heteroaryl is optionally substituted with halogen, C 1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, (CH2)nSO2R12, (CH2)nC(O)R12, (CH2)nC(O)OR12, or (CH2)nC(O)N(R12)2, or two R10, together with the atoms to which they are attached, form a C3-C10cycloalkyl, an aryl, a heterocycle comprising 1-4 heteroatoms selected from O, N, and S, or a heteroaryl, wherein the cycloalkyl, aryl, heterocycle, and heteroaryl are optionally substituted with one or more 12, halogen, CN, NO2, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1- C6haloalkyl, C1-C6alkoxy, (CH2)nOR12, (CH2)nN(R12)2, (CH2)nC(O)R12, (CH2)nC(O)OR12, (CH2)nC(O)N(R12)2, (CH2)nSO2R12, C3-C6cycloalkyl, aryl, heteroaryl, or R15; R11is H, C1-C6alkyl, C2-C6alkenyl, or C2-C6alkynyl; each R12and R13at each occurrence is independently H, C1-C6alkyl, C2-C6alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, (CH2)q O C(O) (CH2)r R14, (CH2)qNH C(O) (CH2)r R14, (CH2)q O C(O) (CH2)r OR14, (CH2)q NH C(O)(CH2)r OR14, (CH2)q O (CH2)r R14, (CH2)q NH (CH2)r R14, (CH2)q O(CH2)r OR14, (CH2)q NH (CH2)r OR14, C3-C10 cycloalkyl, heterocycle comprising 1-4 heteroatoms selected from O, N, and S, (CH2)q-aryl, or heteroaryl comprising 1-4 heteroatoms selected from N, O, and S, wherein the cycloalkyl, heterocycle, aryl, andWSGR Ref: 64162-710.601 heteroaryl are optionally substituted with one or more halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, or C1-C6haloalkoxy; Ring A is C3-C10cycloalkyl, aryl, heterocycle comprising 1-4 heteroatoms selected from N, O, and S, or heteroaryl comprising 1-4 heteroatoms selected from N, O, and S;two R15, together with the atoms to which they are attached form a cycloalkyl, an aryl, a heterocycle comprising 1-4 heteroatoms selected from O, N, and S, or a heteroaryl, wherein the cycloalkyl, aryl, heterocycle, and heteroaryl are optionally substituted with one or more C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, (CH2)nOR12, (CH2)nN(R12)2, (CH2)nC(O)R12, (CH2)nC(O)OR12, (CH2)nC(O)N(R12)2, or (CH2)nSO2R12; and each n, m, q, r, or s is independently at each occurrence 0, 1, 2, 3, 4, 5, or 6;provided that when R1and R2together with the nitrogen atom to which they are attached form amorpholine and: i. when Y is O ; R3, R4, and R6 are hydrogen; R7 is methyl; X isNR12 and Ring A is aryl; then R5 is not C(O)N(R12)2 or C(O)OR12; ii. when Y is O ,or NR11; R3, R4, R6and R8are hydrogen; R7is H or C1-C6alkyl; X is NR12and Ring A is phenyl or pyridyl; then R5is not H, OH, OCH3, OCF3, F, Cl, CF3, C1-C6alkyl, or (CH2)m-aryl; or iii. when R5is CH3, then either (a) the morpholine is substituted or (b) Ring A is not phenyl.

[0075] to Formula (IV):Formula (IV), or pharmaceutically acceptable salts thereof, wherein: R1is selected from CH3, CH2CH3, CH(CH3)2, CHF2, CH2F, and CF3; X is selected from:WSGR Ref: 64162-710.601where the wavy line indicates the site of attachment; and R2is selected from H, C1-C6alkyl, cyclopropyl, and cyclobutyl, optionally substituted with F, OCH3, or OH.

[0076] comprises a compound disclosedwithin WO2023 / 205680A1, which is herein by reference in their entirety. In some WO2023 / 239846A1, which are herein by reference in their entirety. In some embodiments, WO2023 / 230262A1, which are herein by reference in their entirety. In some embodiments, closed within WO2023 / 168378A1, which are herein by reference in their entirety.

[0077] IC50binding specificity that is 3x or lower, or IC50cell viability -478, which has demonstrated an IC50 of 9.4 nM for , showing14-fold selectivity over wildtype inhibitor is RLY-2608, which has demonstrated an IC50 of 334 nM for , showing 2-foldselectivity over wildtype LOXO-783, which has demonstrated an IC50of 4 nM for , showing 75-fold selectivity over wildtype

[0078] as those disclosed herein (e.g., those cancers comprising a mutation in PIK3CA), in severity of adverse effects, associated with the treatment. e. inhibitor

[0079] In some embodiments, the methods provided herein comprise administering a p110 inhibitor,such as, for example, any of the p110 inhibitors disclosed herein. In some embodiments, theWSGR Ref: 64162-710.601 p110 inhibitor comprises a p110 inhibitor. In some embodiments, the p110 inhibitor

[0080] is a p110 inhibitor that exhibits inhibitive activityagainst . In some embodiments, the inhibitor is a pan-p110 inhibitor (e.g., having inhibitive activity). In some embodiments, the pan-p110 inhibitor comprises pictilisib, copanlisib, dactolisib, apitolisib, bimiralisib, BGT-226, VS-5584, buparlisib, or a combination thereof. In some embodiments, In some embodiments, the inhibitor comprises or . In some embodiments, the inhibitor comprises AZD-6482, AZD-8186, KA-2237, SAR-260301, Apitolisib, BAY-1082439, BGT-226, Bimiralisib, Dactolisib, GSK-2126458, KA-2237, MEN-1611, OP-11, PF-4691502, Pictilisib, Samotolosib, TGX-221, VS-5584, or a combination thereof. In some embodiments, the -6482, TGX-221, SAR-260301, KA-2237, AZD-8186, GSK- STX- -2636771, AZD-6482, or SAR-260301.

[0081] The p110 inhibitor may selectively inhibit p110 or mayinhibit along with one or more other p110 isoforms (e.g., p110 ). In someembodiments, the p110 inhibitor comprises a inhibitor and a second p110 inhibitor. In some embodiments, the second p110 inhibitor comprises a p110 inhibitor of one or more of the other isoforms of p110 (e.g., a p110 inhibitor, a inhibitor, a p110 inhibitor, or acombination thereof). In some embodiments the p110 inhibitor comprises a inhibitor and a inhibitor. In some embodiments, the inhibitor and inhibitor comprises AZD-8186, or KA-2237.

[0082] In some embodiments, the inhibitor is a selective inhibitor. A selectiveinhibitor may target the isoform with at least a 3x higher selectivity for the isoform (e.g., IC50binding specificity that is 3x or lower, or IC50cell viability that is 3x or lower) compared to other p110 isoforms. For example, the selective inhibitor may inhibit , but provide minimal or no inhibition against p110 alpha, , or . An example of a selective inhibitor is GSK-2636771, which has demonstrated an IC50of 5.2 nM for , showing 900-fold selectivity over -fold selectivity As a further example, AZD-6482, a selective inhibitor, has demonstrated an IC50of 0.69 nM for 200, 20, and 70-fold selectivity for over SAR-260301, a selective inhibitor, has demonstrated an IC50 of 1539, 23, 469, and 10000 nM against p110 ,p110 , p110 , and p110WSGR Ref: 64162-710.601

[0083] In some embodiments, the inhibitor comprises a selective inhibitor. In someembodiments, the selective inhibitor comprises GSK-2636771, AZD-6482, AZD-8186, KA-2237, AZD-8186, KA-2237, or SAR-260301. In some embodiments, the selective inhibitor comprises GSK-2636771, AZD-6482, or SAR-260301. In some embodiments, the selective inhibitor comprises GSK-2636771. In some embodiments, the selective inhibitor comprises AZD-6482. In some embodiments, the selective inhibitor comprises KA-2237. In some embodiments, the selective inhibitor comprises AZD- 8186. In some embodiments, the selective inhibitor comprises SAR-260301.

[0084] s include, but are not limited to, thosedisclosed in U.S. patent number 10,526,316 Quinoxaline and pyridopyrazine15 / 766887), U.S. patent number 10,894,793 Bicyclic pyridine, pyrazine, and pyrimidine derivatives as PI3K inhibitorsnumber 16 / 309999), U.S. application number 16 / 310413 Azabenzimidazole derivatives as PI3K inhibitors US10087187B2 (entitledImidazopyridazine derivatives as PI3KB inhibitors number 15 / 537551), and WO2020048409A1 ( 1,5-naphthyridin-4(1H)-onederivatives as PI3K inhibitorsPCT / CN2019 / 103904), each of which is incorporated by reference herein in its entirety.

[0085] In some embodiments, is a compound of Formula (VI)a tautomer or a stereoisomeric form thereof, wherein Y represents CR3or N; L represents CH(C1-4alkyl)-CH2, CH2CH(C1-4alkyl)-, CH(C1-4alkyl)-CH(C1-4-alkyl)-, CHR1a X , or X CHR1c ;X represents O, S, or NR1b; R1arepresents hydrogen, C1-4alkyl, or C1-4alkyl substituted with one OH; R1crepresents hydrogen or C1-4alkyl; R1brepresents hydrogen, C1-4-alkyl, CH2NR6aR6b, or C1-4alkyl substituted with one substituent selected from the group consisting of hydroxyl, O C1-4alkyl, andNR6cR6d;WSGR Ref: 64162-710.601 or R1bis taken together with R1aor R1cto form (CH2)3; or R1bis taken together with R1cto form (CH2)2or (CH2)4;R2 representsR6aand R6beach independently are selected from the group consisting of hydrogen and C1-4alkyl;R6c and R6d each independently are selected from the group consisting of hydrogen,C1-4alkyl, and C1-4alkyl substituted with one substituent selected from the group consisting of hydroxyl, NH2, NH(C1-4alkyl), and N(C1-4alkyl)2; R3represents R7, C1-4alkyl, NR5aR5b, OR5c, -Het1, NH-Het2, NH C1-4alkyl-Het1,N(C1-4alkyl)-C1-4alkyl-Het1, N(C1-4-alkyl)-Het2, C1-4alkyl,OH, CH(OH) CH2 NR5dR5e, CH(OH) CH2-Het1, CH(OH) C1-4alkyl,C(OH)(C1-4alkyl)2, halo, or R3represents C1-4alkyl substituted with one substituent selectedfrom the group consisting of hydroxyl, fluoro,C1-4alkyl, O CH(NH2) C1-and O C1-4alkyl-NH2;R5a and R5b each independently are selected from the group consisting of hydrogen,C1-4alkyl, O C1-4-alkyl, 2 NH2, 2 C1-4alkyl, 2 C3-6cycloalkyl, C1-4alkyl substituted with one or more halo atoms, and C1-4alkyl substituted withone substituent selected from the group consisting of hydroxyl, O C1-4alkyl, 2C1-4alkyl, O C1-4alkyl-NH2, O C1-4alkyl-NH(C1-4alkyl), O C1-4alkyl-N(C1-4alkyl)2,O C1-4alkyl, OH, C1-4alkyl, NH2, NH(C1-4alkyl) andN(C1-4alkyl)2; R5crepresents hydrogen or C1-4alkyl; R5dand R5eeach independently are selected from the group consisting of hydrogen and C1-4alkyl; R5fand R5eeach independently are selected from the group consisting of hydrogen,C1-4alkyl,C1-4alkyl substituted with one or more halo atoms, and C1-4alkyl substituted with onesubstituent selected from the group consisting of hydroxyl, O C1-4alkyl, 2 C1-4alkyl, NH2, NH(C1-4alkyl), and N(C1-4alkyl)2;WSGR Ref: 64162-710.601 R4a, R4band R4ceach independently are selected from the group consisting of hydrogen,cyano, C1-4alkyl, halo, NR6cR6f, O C1-4alkyl, and C1-4alkyl substituted withone or more substituents each independently selected from the group consisting of hydroxyl, halo, and NR6gR6h; R6eand R6feach independently are selected from the group consisting of hydrogen, C1-4alkyl, and C1-4alkyl substituted with one substituent selected from the group consisting of NH2, NH(C1-4alkyl), and hydroxyl; R6gand R6heach independently are selected from the group consisting of hydrogen, C1-4alkyl, and C1-4alkyl substituted with one substituent selected from the group consisting of NH2, NH(C1-4alkyl), and hydroxyl; Het1represents a monocyclic 4-, 5-, 6- or 7-membered saturated or partially saturated heterocyclyl containing at least one heteroatom each independently selected from O, S, p and N; or Het1represents a bicyclic 8-, 9- or 10-membered saturated or partially saturated heterocyclyl containing at least one heteroatom each independently selected from O, p and N; each optionally substituted with one or two substituents each independently selected from the group consisting of halo, NR9aR9b, C1-4alkyl, OR5h,2C1-6alkyl, C1-4alkyl- 2 C1-6alkyl, hydroxyl, O C1-4alkyl, cyano, C1-4 alkyl substituted with one ormore halo atoms, and C1-4alkyl substituted with one substituent selected from the group consisting of hydroxyl, NH2, NH(C1-4alkyl) and N(C1-4alkyl)2; or two substituents on the same carbon atom of said heterocyclyl are taken together to form together with the common carbon atom to which they are attached Ring A; R9aand R9beach independently are selected from the group consisting of hydrogen, C1-4alkyl, and C1-4alkyl substituted with one or more halo atoms; Het2representsn1 represents 1 or 2; n2 represents 1 or 2; R8represents hydrogen, C1-4alkyl, or C1-4alkyl substituted with one or more halo atoms; R5hrepresents hydrogen or C1-4alkyl; Ring A represents cyclobutyl, cyclopentyl, cyclohexyl, or a 4-, 5- or 6-membered saturated heterocyclyl containing at least one heteroatom each independently selected from O, S, p and N; said cyclobutyl, cyclopentyl, cyclohexyl, or 4-, 5- or 6-membered saturated heterocyclyl is optionally substituted with one or two C1-4alkyl substituents, with one C1-4and one hydroxy substituent, or with one hydroxy substituent;WSGR Ref: 64162-710.601 p represents 1 or 2; Ar represents phenyl optionally substituted with one hydroxyl; R7 representsacceptable addition salt or a solvate thereof.

[0086] In some embodiments, the is a compound of Formula (VI)a tautomer or a stereoisomeric form thereof, wherein X1represents CH; X2represents N; Yrepresents CH2 or NH ;R2representsR3 represents C1-4alkyl; O C1-4alkyl; Het1; CH(OH) CH2 Rq;C1-4alkyl substituted on the same carbon atom with one OH and with one Het1; or C1-4alkyl substituted with one substituent selected from the group consisting of halo, OH, NH2, OC1-4alkyl, O C1-4 - C1-4alkyl, NH (SO2)C1-4alkyl, N(CH3) C1-4alkyl-SO2 CH3, NH C1-4alkyl-SO2 CH3, N(CH3) C1-4alkyl-OH, C1-4alkyl)-C1-4alkyl-OH, NH C1-4alkyl-OH,WSGR Ref: 64162-710.601Ar represents phenyl optionally substituted with one hydroxy; R4arepresents hydrogen, C1-4alkyl, Heta, or C1-4alkyl substituted with one or more substituents each independently selected from the group consisting of OH, NR5R6and Heta; R4brepresents hydrogen, halo, C1-4alkyl, or C1-4alkyl substituted with one or more halo substituents; or R4a and R4bare taken together to form together with the phenyl ring to which they are attached a structure of Formula (a-1), (a-2), (a-3), (a-4) or (a-5):X represents NH , O , N(C1-3alkyl)-, or N(hydroxyC1-3alkyl)-;both R7substituents are the same and are selected from the group consisting of hydrogen, fluoro and methyl; or both R7substituents are taken together to form together with thecommon carbon atom to which they are attached a cyclopropyl, cyclobutyl or oxetanyl;WSGR Ref: 64162-710.601 both R8substituents are the same and are selected from the group consisting of hydrogen and methyl; or both R8substituents are taken together to form together with the common carbon atom to which they are attached a cyclopropyl, cyclobutyl or oxetanyl; R5represents hydrogen, C1-6alkyl, or C1-6alkyl substituted with one OH; R6represents hydrogen, C1-6alkyl, or C1-6alkyl substituted with one OH; Het1represents a 4-, 5- or 6-membered saturated heterocyclyl containing at least one p and N; said 4-, 5- or 6-membered saturated heterocyclyl is optionally substituted with one or two substituents each independently selected from the group consisting of halo, NH2, C1-4alkyl, 2C1-6alkyl, C1-4alkyl- 2 C1-6alkyl hydroxyl, C1-4alkyloxy, fluoro, cyanoand C1-4alkyl substituted with one hydroxy; or two substituents on the same carbon atom of said 4-, 5- or 6-membered saturated heterocyclyl are taken together to form together with the common carbon atom to which they are attached Ring A; Ring A represents cyclobutyl, cyclopentyl, cyclohexyl or a 4-, 5- or 6-membered saturated heterocyclyl containing at least one heteroatom each independently selected from O, S,pand N; said cyclobutyl, cyclopentyl, cyclohexyl or 4-, 5- or 6-membered saturated heterocyclyl is optionally substituted with one or two C1-4alkyl substituents, with one C1-4alkyl and one hydroxy substituent, or with one hydroxy substituent; each Heta independently represents a 4-, 5- or 6-membered saturated heterocyclyl containingpand N; said 4-, 5- or 6- membered saturated heterocyclyl is optionally substituted with one or two substituents each independently selected from the group consisting of C1-4alkyl,2-C1-6alkyl, hydroxy, C1-4alkyl- 2 C1-6alkyl, and C1-4alkyl substituted with one hydroxy; or twosubstituents on the same carbon atom of said 4-, 5- or 6-membered saturated heterocyclyl are taken together to form together with the common carbon atom to which they are attached Ring B; Ring B represents cyclobutyl, cyclopentyl, cyclohexyl or a 4-, 5- or 6-membered saturated heterocyclyl containing at least one heteroatom each independently selected from O, S, p and N; said cyclobutyl, cyclopentyl, cyclohexyl or 4-, 5- or 6-membered saturated heterocyclyl is optionally substituted with one or two C1-4alkyl substituents, with one C1- 4alkyl and one hydroxy substituent, or with one hydroxy substituent; p represents 1 or 2; or a N-oxide, a pharmaceutically acceptable addition salt thereof.

[0087] In some embodiments, is a compound of Formula (VII)WSGR Ref: 64162-710.601a tautomer or a stereoisomeric form thereof, whereinR3 represents C1-4alkyl; CH(OH) CH2 Rq; C1-4alkyl substituted on the same carbon atomwith one OH and with one Het1; or C1-4alkyl substituted with one substituent selected fromthe group consisting of fluoro, OH, NH2, O C1-4alkyl, O C1-4alkyl, NH C1-4alkyl, NH (SO2) C1-4alkyl, N(CH3) C1-4alkyl-SO2CH3, NH C1-4alkyl-SO2 CH3, N(CH3) C1-4alkyl-OH, NH C1-4alkyl-and NH Het1;Rq represents Het1, fluoro, OH, NH2, O C1-4alkyl, NH C1-4 alkyl, NH (SO2) C1-4alkyl, N(CH3) C1-4alkyl-SO2 CH3, NH C1-4alkyl-SO2Ar represents phenyl optionally substituted with one hydroxy; R4arepresents hydrogen, C1-4alkyl, Het1, or C1-4alkyl substituted with one or more substituents each independently selected from the group consisting of OH, NR5R6and Het1; R4brepresents hydrogen, halo, C1-4alkyl, or C1-4alkyl substituted with one or more halo substituents;WSGR Ref: 64162-710.601 or R4aand R4bare taken together to form together with the phenyl ring to which they are attached a structure of Formula (a-1), (a-2), (a-3), (a-4) or (a-5):X represents NH , O , N(C1-3alkyl)-, or N(hydroxyC1-3alkyl)-;both R7substituents are the same and are selected from the group consisting of hydrogen, fluoro and methyl; or both R7substituents are taken together to form together with thecommon carbon atom to which they are attached a cyclopropyl, cyclobutyl or oxetanyl;both R8substituents are the same and are selected from the group consisting of hydrogen and methyl; or both R8substituents are taken together to form together with the common carbon atom to which they are attached a cyclopropyl, cyclobutyl or oxetanyl; R5represents hydrogen, C1-6alkyl, or C1-4alkyl substituted with one OH; R6represents hydrogen, C1-6alkyl, or C1-4alkyl substituted with one OH; Het1represents a 4-, 5- or 6-membered saturated heterocyclyl containing at least one p and N; said 4-, 5- or 6-memberedWSGR Ref: 64162-710.601 saturated heterocyclyl is optionally substituted with one or two substituents each independently selected from the group consisting of halo, NH2, C1-4alkyl,2C1-6alkyl, C1-4alkyl- 2 C1-6alkyl, hydroxyl, C1-4alkyloxy, fluoro, cyano and C1-4 alkylsubstituted with one hydroxy; or two substituents on the same carbon atom of said 4 -, 5- or 6-membered saturated heterocyclyl are taken together to form together with the common carbon atom to which they are attached Ring A; Ring A represents cyclobutyl, cyclopentyl, cyclohexyl or a 4-, 5- or 6-membered saturated heterocyclyl containing at least one heteroatom each independently selected from O, S, p and N; said cyclobutyl, cyclopentyl, cyclohexyl or 4-, 5- or 6-membered saturated heterocyclyl is optionally substituted with one or two C1-4alkyl substituents, with one C1-4alkyl and one hydroxy substituent, or with one hydroxy substituent; each Het1 independently represents a 4-, 5- or 6-membered saturated heterocyclyl containingpand N; said 4-, 5- or 6- membered saturated heterocyclyl is optionally substituted with one or two substituents each independently selected from the group consisting of C1-4alkyl,2C1-6alkyl, hydroxy, C1-4alkyl- 2 C1-4alkyl, and C1-4alkyl substituted with one hydroxy; or twosubstituents on the same carbon atom of said 4-, 5- or 6-membered saturated heterocyclyl are taken together to form together with the common carbon atom to which they are attached Ring B; Ring B represents cyclobutyl, cyclopentyl, cyclohexyl or a 4-, 5- or 6-membered saturated heterocyclyl containing at least one heteroatom each independently selected from O, S, p and N; said cyclobutyl, cyclopentyl, cyclohexyl or 4-, 5- or 6-membered saturated heterocyclyl is optionally substituted with one or two C1-4alkyl substituents, with one C1-4alkyl and one hydroxy substituent, or with one hydroxy substituent; p represents 1 or 2; or a N-oxide, a pharmaceutically acceptable addition salt or a solvate thereof.

[0088] In some embodiments, is a compound of Formula (VIII)a tautomer or a stereoisomeric form thereof, whereinWSGR Ref: 64162-710.601Y represents CH2 or NH ;R4arepresents hydrogen, C1-4alkyl, Heta, or C1-4alkyl substituted with one or more substituents each independently selected from the group consisting of OH, NR5R6and Heta; R4brepresents hydrogen, halo, C1-4alkyl, or C1-4alkyl substituted with one or more halo substituents; or R4aand R4bare taken together to form together with the phenyl ring to which they are attached a structure of Formula (a-1), (a-2), (a-3), (a-4) or (a-5):WSGR Ref: 64162-710.601X represents NH , O or N(C1-3alkyl)-;both R7substituents are the same and are selected from the group consisting of hydrogen, fluoro and methyl; or both R7substituents are taken together to form together with thecommon carbon atom to which they are attached a cyclopropyl, cyclobutyl or oxetanyl;both R8substituents are the same and are selected from the group consisting of hydrogen and methyl; or both R8substituents are taken together to form together with the common carbon atom to which they are attached a cyclopropyl, cyclobutyl or oxetanyl; R5represents hydrogen, C1-6alkyl, or C1-6alkyl substituted with one OH; R6represents hydrogen, C1-6alkyl, or C1-6alkyl substituted with one OH; Ar represents phenyl optionally substituted with hydroxy;each Heta independently represents a 4-, 5- or 6-membered saturated heterocyclyl containingpand N; said 4-, 5- or 6- membered saturated heterocyclyl is optionally substituted with one or two substituents each independently selected from the group consisting of C1-4alkyl,2C1-6alkyl, hydroxy, C1-4alkyl- 2 C1-6alkyl, and C1-4alkyl substituted with one hydroxy; or twosubstituents on the same carbon atom of said 4-, 5- or 6-membered saturated heterocyclyl are taken together to form together with the common carbon atom to which they are attached Ring B; Ring B represents cyclobutyl, cyclopentyl, cyclohexyl or a 4-, 5- or 6-membered saturated heterocyclyl containing at least one heteroatom each independently selected from O, S, p and N; said cyclobutyl, cyclopentyl, cyclohexyl or 4-, 5- or 6-membered saturatedWSGR Ref: 64162-710.601 heterocyclyl is optionally substituted with one or two C1-4alkyl substituents, with one C1-4alkyl and one hydroxy substituent, or with one hydroxy substituent; p represents 1 or 2; or a N-oxide, a pharmaceutically acceptable addition salt or a solvate thereof.

[0089] In some embodiments, is a compound of Formula (V),or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein: R1 is halogen, C1-6alkyl, or C3-6cycloalkyl;m is 0, 1, 2, 3 or 4;R2 is halogen, C1-6alkyl, or C3-6cycloalkyl;n is 0, 1 or 2; R3is halogen, C1-6alkyl optionally substituted with halogen, or C3-6cycloalkyl; p is 0, 1, 2, 3, 4, or 5; L1is -C1-4alkylene-, wherein one -CH2-moiety is optionally replaced with -O-, -S-or -NH-; R4and R5are each independently hydrogen, halogen, C3-6cycloalkyl, -CONR6R7, or C1-6alkyl optionally substituted with halogen; R6is hydrogen or C1-6alkyl; and R7is hydrogen, C1-6alkyl, C3-6cycloalkyl, aryl, heteroaryl, or heterocyclyl, each of said C1-6alkyl, C3-6cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with R7a; or R6 and R7, together with the nitrogen atom to which they are attached, form a 4- to 12-membered ring, said ring comprising 0, 1 or 2 additional heteroatoms independently selected f rom nitrogen, oxygen or optionally oxidized sulfur as ring member (s) , said ring is optionallysubstituted with one or two substituents R8; R7ais aryl, heteroaryl, heterocyclyl, NRaRb, C3-6cycloalkyl, C1-6alkoxy, or hydroxy, each of said aryl, heteroaryl, and heterocyclyl is optionally substituted with halogen, C1-6alkyl or C1-6alkoxy; R8 is C1-6alkyl, said C1-6alkyl is optionally substituted with halogen, C3-6cycloalkyl or NRcRd;Ra and Rb are each independently hydrogen or C1-6alkyl; andWSGR Ref: 64162-710.601 Rc and Rd are each independently hydrogen or C1-6alkyl.

[0090] In some embodiments, the compound of Formula (V) is selected from:WSGR Ref: 64162-710.601WSGR Ref: 64162-710.601 , or a pharmaceutically acceptable salt thereof.

[0091] A selective inhibitor may be useful in treating a cancer (e.g., cancers comprising amutation in PIK3CA), while potentially lowering the incidence or severity of adverse effects, associated with the treatment. f.

[0092] Provided herein are methods for treating a cancer in a subject, comprising administering p110inhibitors, such as, for example, any of the mutant selective p110 inhibitors disclosed herein.WSGR Ref: 64162-710.601 In some embodiments, the p110 inhibitor comprises a mutant selective comprises STX-478, RLY-2608, LOXO-783, SNV-4818, inavolisib, or a combination thereof . In some embodiments, theis a p110 inhibitor that exhibits inhibitive activity against . In some embodiments, the p110 inhibitor is a pan-p110 inhibitor (e.g., having inhibitiveactivity). In some embodiments, the pan-p110 inhibitor comprises pictilisib, copanlisib, dactolisib, apitolisib, bimiralisib, BGT-226, VS-5584, buparlisib, or a combination thereof. In some embodiments, In some embodiments, the inhibitor comprises or . In some embodiments, the inhibitor comprises AZD-6482, AZD-8186, KA-2237, SAR-260301, Apitolisib, BAY-1082439, BGT-226, Bimiralisib, Dactolisib, GSK- 2126458, KA-2237, MEN-1611, OP-11, PF-4691502, Pictilisib, Samotolosib, TGX-221, VS- 5584, or a combination thereof. In some embodiments, AZD- 6482, TGX-221, SAR-260301, KA-2237, AZD-8186, GSK-2636771, or a combination thereof. - inhibitor is not GSK-2636771, AZD-6482, or SAR-260301.

[0093] Provided herein are methods for treating a cancer in a subject, comprising administering p110inhibitors, such as, for example, any of the p110 inhibitors disclosed herein, wherein the said subject, wherein said administering exhibits a synergistic effect.

[0094] Provided herein are methods for treating a cancer in a subject, comprising administering p110inhibitors, such as, for example, any of the p110 inhibitors disclosed herein, wherein the inhibitor compared to a corresponding corresponding administration of sai inhibitor. In some e effect is on inhibiting tumor growth. In some embodiments, said inhibition of tumor growth is exhibited for at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 21, 28, 30, 50, 75, 100, 200, 250, 300, 365 days. In some embodiments, said inhibition of tumor growth is exhibitedWSGR Ref: 64162-710.601 for about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 21, 28, 30, 50, 75, 100, 200, 250, 300, 365 days.

[0095] In some embodiments, said synergistic effect inhibits cellular proliferation of cells comprisingular proliferation of cells effect increases inhibition of cellular proliferation of cells compared to ce In some embodiments, said synergistic effectresults to achieve inhibition compared to a dosage of either In some embodiments, said lower dosage results in an improved

[0096] In some embodiments, said administering inhibits tumor growth more than a correspondingembodiments, said administering increases said cancer cell inhibition compared to a embodiments, said administering increases said cancer cell inhibition compared to a inhibitor. In some embodiments, said administering increases said cancer cell inhibition cell inhibition is increased by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 97%, 98%, 99%, 100%, 200%, 300%, 400%, or 500%. In some embodiments, said cancer cell inhibition is increased by about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 97%, 98%, 99%, 100%, 200%, 300%, 400%, or 500%.

[0097] Provided herein are methods for treating a cancer in a subject, comprising administering p110inhibitors, such as, for example, any of the p110 inhibitors disclosed herein, wherein the in said subject has inhibitor to said subject. In some embodiments, said cancer was previously determined not to cancer was determined to increase in a size or increase in a rate of growth.

[0098] Provided herein are methods for treating a cancer in a subject, comprising administering p110inhibitors, such as, for example, any of the p110 inhibitors disclosed herein, wherein theWSGR Ref: 64162-710.601 inhibitor. In some embodiments, a tumor of said cancer was determined to increase in a size or increase in a rate of growth.

[0099] -478, RLY-2608,LOXO-783, SNV-4818, inavolisib, or a combination thereof. In some embodiments, said -478. In some embodiments, said mutant -2608. In some embodiments, said mutant selective XO- inhibitor comprises SNV- nhibitorcomprises inavolisib. inhibitor comprises a compound according to Formula II. In some embodiments, said mutant selective p110 Formula IV. AZD-6482, TGX-221, SAR-260301, KA-2237, AZD-8186, GSK-2636771, or a combination thereof. In -6482. In some -221. In some embodiments, said - inhibitor comprises KA-2237. In some embodiments, said selective p1 AZD- GSK-2636771. Inis a compound of Formula (V). In some is a compound of Formula (VI). In some is a compound of Formula (VII). In some is a compound of Formula (VIII).

[0100] inhibitor for at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 21, 28, 30, 50, 75, 100, 200, 250, 300, 365 days. In some embodiments, said administering increases an activity of 28, 30, 50, 75, 100, 200, 250, 300, 365 days. g. PIK3CA Gene

[0101] p110 may add a cluster of oxygen and phosphorus atoms (a phosphate group) to other proteinsthrough phosphorylation. p110 phosphorylates certain signaling molecules, which may triggerWSGR Ref: 64162-710.601 a series of additional reactions that transmit chemical signals within cells. p110 signaling may be important for many cell activities, including cell growth and division (proliferation), movement (migration) of cells, production of new proteins, transport of materials within cells, and cell survival. Studies suggest that p110 signaling may also be involved in the regulation of several hormones and may even play a role in the maturation of fat cells (adipocytes).

[0102] In some embodiments, the methods of treating a cancer provided herein comprise treating acancer comprising a mutation in a PIK3CA gene. In some embodiments, the method further comprises determining if the patient (e.g., a cancer cell or tumor of the patient) has a mutation in a PIK3CA gene. In some embodiments, the methods of treating a cancer provided herein comprise treating a cancer comprising a mutation in a Phosphatidylinositol-4,5-Bisphosphate 3- PIK3CA . A PIK3CA mutation is a geneticalteration in the PIK3CA gene that may result in a change in the protein sequence.

[0103] In some embodiments, the mutation is a gain of function mutation. In some embodiments, thegain of function mutation comprises a new function of the protein compared to wildtype. In some embodiments, the gain of function mutation comprises a different function of the protein compared to wildtype. In some embodiments, the gain of function mutation comprises a change in protein levels compared to wildtype. In some embodiments, the gain of function mutation comprises an increase in protein levels compared to wildtype. In some embodiments, the gain of function mutation comprises an decrease in protein levels compared to wildtype. In some embodiments, the gain of function mutation comprises an change in signaling levelscompared to wildtype. In some embodiments, the gain of function mutation comprises an increase in signaling levels compared to wildtype. In some embodiments, the gain of function mutation comprises an increase in downstream signaling compared to wildtype. In some embodiments, the gain of function mutation comprises an increase in the genomic copies of a PIK3CA gene. In some embodiments, the gain of function mutation comprises an mutation in a PIK3CA gene. In some embodiments, the gain of function mutation comprises aberrant regulation or dysregulation of the protein compared to wildtype.

[0104] The PIK3CA gene may be an important gene in the PI3K pathway, as it may provideinstructions for making the p110 alpha ( ) protein, which is one piece (subunit) of thep110 enzyme. The protein, sometimes called the catalytic subunit, performs the actionof p110, while the other subunit (produced by a different gene) regulates the enzyme's activity. Therefore, the PIK3CA gene may be an important target in treating a cancer.

[0105] PIK3CA mutations have been identified in a variety of human cancers, including, but notlimited to, breast, colon, ovarian, and endometrial cancers, and PIK3CA mutations are one ofthe most frequently mutated genes in human cancers.WSGR Ref: 64162-710.601

[0106] p110 signaling may be important for normal cell function and dysregulation of this pathwaycan contribute to cancer development and progression. PIK3CA mutations are one mechanismby which the p110 / AKT / mTOR pathway can become dysregulated in cancer. Targeting this pathway with drugs that inhibit p110, AKT, or mTOR is an area of active research in cancer therapy, with a number of compounds targeting various nodes in the relevant pathway having been developed. In some embodiments, the mutation comprises a change in the signaling levels of the p110 / AKT / mTOR pathway. In some embodiments, the mutation comprises an increase in phosphorylation of proteins in the p110 / AKT / mTOR pathway.

[0107] Although p110 inhibitors provide a promising area of research in the study of cancer, thedevelopment of resistance to p110 inhibitors remains a significant challenge. Many of the relevant compounds have been unsuccessful in patients due to high levels of toxicity or their inability to downregulate the PI3K pathway. Studies have shown that cancers can disregard the downregulation of the PI3K pathway by either maintaining or re-establishing activation of the targeted pathway or by inducing alternate signaling pathways. In fact, a number of studies have shown that short-term treatments can result in the activation of feedback loops that subsequently decrease overall response rates, and that chronic administration of these therapies may result in the establishment of a reservoir of slow cycling cells that eventually may acquire resistance-conferring genetic mutations. It has also been observed in clinical application that toxicities are likely caused by inhibition of wildtype p110 other p110 variants, suggesting that a narrow therapeutic index may also pose additional challenges. Accordingly, there is a need to identify and research means for overcoming resistance to p110 inhibitors.

[0108] One strategy to overcome challenges associated with cancers associated with PIK3CA genemutations may be through combination therapy. Since many cancer cells already have a mutated PIK3CA gene, a promising approach is to identify and then pharmacologically target a mutated PIK3CA gene. Surprisingly, the current inventors have discovered that cancer cells possessing a PIK3CA mutation are unexpectedly susceptible to simultaneous inhibition of mutant p110 In some embodiments, the mutation is a gain of functionmutation.

[0109] In some embodiments, the mutation (e.g., gain of function mutation) is in a PIK3CA gene. Insome cases, the mutation of a PIK3CA gene results in development of a cancer. In some embodiments, the mutation is a gain of function mutation.

[0110] In some embodiments, said cancer comprises a mutation in the gene. In some embodiments,the mutation is in a PIK3CA gene. In some embodiments, the mutation is a gain of functionmutation. As used herein, a gain of function mutation may refer to a mutation in a gene thatWSGR Ref: 64162-710.601 results in an increased function of the gene, an increased function of a product of the gene, or an increased production of a product of the gene (e.g., an amount of protein produced by the gene (e.g., )).

[0111] In some embodiments, the method of treating a cancer in a patient in need thereof comprisesdetermining whether the patient has a mutation (e.g., GOF mutation), for example by obtaining or having obtained a biological sample form the patient, and if the patient has the mutation of the PIK3CA gene, then administering a first p110 inhibitor and a second p110 inhibitor (e.g., a mutant selective p110 inhibitor). In someembodiments, said method further comprises performing or having perfo rmed a test (e.g.,assay) on the biological sample to determine if the patient has the mutation (e.g., GOF mutation) of the PIK3CA gene.

[0112] In some embodiments, the mutation comprises a change of residue located at aminoacid position 38, 81, 88, 93, 104, 106, 108, 111, 118, 344, 345, 350, 365, 420, 453, 539, 542, 545, 546, 726, 901, 1004, 1021, 1025, 1043, 1044, 1047, or 1049 compared to wildtype. In some embodiments, the mutation amino acid position 38 in some embodiments, the mutation comprises a change of residue of comprises a ch position in some embodiments, in some embodiments, the mutation comprises a change of residue of p110 emb ated at amino acid position 104, in some embodiments, the mutation comprises a change of residue of me embodiments, the position 118, in some embodiments, the mutation comprises located at amino acid position 344, in some embodiments, the mutation comprises a change ofWSGR Ref: 64162-710.601 located at amino acid position 420, in some embodiments, the mutation comprises a change of n some located at amino acid position 545, in some embodiments, the mutation comprises a change of ted at amino acid located at amino acid position 1004, in some embodiments, the mutation comprises a change ome embodiments, the mutation position 1043, in some embodiments, the mutation compri located at amino acid position 1044, in some embodiments, the mutation comprises a change ated at amino acid position 1049. In some E545K Q546K G1049R T1025S R93Q N345TH1047R G118D K111E N1044K Q546P P104LE542K E453K R93W V344G E545Q D350GR88Q Q546R H1047Y G106V R38H M1004VH1047L M1043V Y1021H E365K E545DN345K R108H V344M K111N M1004IC420R E81K E545A P539R Q546HE726K E545G M1043I R38C C901F

[0113] In some embodiments, the mutation is a glutamate to any other amino acid mutation at aminomutation is aWSGR Ref: 64162-710.601 some embodiments, the mutation is a glutamate to lysine mutation at amino acid position 545 ts, the In some embodiments, the mutation is a histidine to leucine mutation at amino acid position istidine to tyrosine mutation at amino acid position 1047 (H1047Y) of

[0114] In some embodiments, the method of treating a cancer in a patient in need thereof comprisesdetermining whether the patient has an increased amount, function, or signaling activity of (e.g., by obtaining or having obtained a biological sample form the patient), and if the patient has the increased amount, function, or signaling activity of , then administering a first p110 inhibitor and a second p110 inhibitor (e.g., a mutant selective selective inhibitor). In some embodiments, said method further comprises performing or having performed a test (e.g., assay) on the biological sample to determine if the patient has the increased amount, function, or signaling activity of . h.

[0115] Provided herein, in some embodiments, is a method of treating a cancer in a patientcomprising an increased amount, function, or signaling activity of . In some embodiments, the method further comprises determining if the patient (e.g., a cancer cell or tumor of the patient) has an increased amount, function, or signaling activity of . is a product of PIK3CA. In some embodiments, the gain of function mutation in a PIK3CA gene increases an amount, function, or signaling activity of . In some embodiments, the increased amount, function, or signaling activity of is a result of a mutation of a PIK3CA gene. In some embodiments, a cancer causes the increased amount, function, or signaling activity of p110 In some embodiments, the treatment is with a different medication (e.g., other than a ainhibitor). In some embodiments, the different medication is administered before ainhibitor. In some embodiments, the patient (e.g., a cancer cell or tumor of the patient) has been previously determined as comprising an increased amount, function, or signaling activity of .

[0116] In some embodiments, said patient (e.g., a cancer cell or tumor of the patient) has an increasedamount, function, or signaling activity of (e.g., as compared to a wild-type amount, function, or signaling activity of ). In some embodiments, said patient (e.g., a cancercell or tumor of the patient) has been previously determined as comprising an increasedWSGR Ref: 64162-710.601 amount, function, or signaling activity of (e.g., as compared to a wild-type amount, function, or signaling activity of ). In some embodiments, the method comprises administration of a composition comprising a first p110 inhibitor and a second p110 inhibitor.

[0117] In some embodiments, the cancer comprises a mutation of a PIK3CA gene. In someembodiments, the method further comprises determining if the patient (e.g., a cancer cell or tumor of the patient) has a mutation of a PIK3CA gene. In some embodiments, the mutation is a gain of function mutation. In some embodiments, the mutation of a PIK3CA gene (e.g., wherein said mutation of the PIK3CA gene causes or is a result of the cancer) causes an increased amount, function, or signaling activity of (e.g., as compared to a wild-type amount, function, or signaling activity in the patient (e.g., a cancer cell or tumor of the patient)).

[0118] In some embodiments, the patient, or a cancer cell of the patient, has been determined tocomprise an amount of that is increased compared to a wild-type amount of . In some embodiments, the patient, or a cancer cell of the patient, has been determined to comprise an amount of that is increased compared to the average amount of p110 protein in tissue of origin-matched tumors with wild-type . In some embodiments, patient (e.g., a cancer cell of the patient) has been determined to comprise an increased amount of function compared to a wild-type amount of function.

[0119] In some embodiments, the increased amount, function, or signaling activity of is aresult of a mutation of a PIK3CA gene (e.g., that causes or is caused by a cancer).i. Types of Cancer

[0120] A mutation of a PIK3CA gene may result in a cancer or may exacerbate the severity ormetastasis of the cancer. The methods provided herein may be useful in the treatment of a cancer, such as a cancer comprising a mutation (e.g., a gain of function mutation) in a PIK3CA gene of a PIK3CA gene. These methods may be useful in the treatment of cancer, such as a cancer comprising an increased amount of or function of . In some embodiments, the mutation is a gain of function mutation.

[0121] Evidence for a PIK3CA gain of function mutation may be manifested as increased p110signaling. Evidence has demonstrated that a gain of function in a gene is particularlystrong in endometrial cancer, breast cancer, cervical cancer, anal cancer, vaginal cancer, small bowel cancer, bladder cancer, colorectal cancer, head and neck cancer, breast sarcoma, salivary gland cancer, ampullary cancer, skin cancer, melanoma, non-melanoma, cancer of unknown primary, ovarian cancer, glioma, embryonal tumor, gastric cancer, esophagogastric cancer, small cell lung cancer, appendiceal cancer, miscellaneous neuroepithelial tumor, non-WSGR Ref: 64162-710.601 small cell lung cancer, soft tissue sarcoma, thyroid cancer, and prostate cancer, for example. In some embodiments, the cancer is endometrial cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is cervical cancer. In some embodiments, the cancer is anal cancer. In some embodiments, the cancer is vaginal cancer. In some embodiments, the cancer is small bowel cancer. In some embodiments, the cancer is bladder cancer. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is head and neck cancer. In some embodiments, the cancer is breast sarcoma. In some embodiments, the cancer is salivary gland cancer. In some embodiments, the cancer is ampullary cancer. In some embodiments, the cancer is skin cancer. In some embodiments, the cancer is non-melanoma. In some embodiments, the cancer is cancer of unknown primary. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is glioma. In some embodiments, the cancer is embryonal tumor. In some embodiments, the cancer is esophagogastric cancer. In some embodiments, the cancer is small cell lung cancer. In some embodiments, the cancer is appendiceal cancer. In some embodiments, the cancer is miscellaneous neuroepithelial tumor. In some embodiments, the cancer is non-small cell lung cancer. In some embodiments, the cancer is prostate cancer.

[0122] Provided herein are methods of treating a cancer in a subject, where said cancer comprisesendometrial cancer, breast cancer, cervical cancer, anal cancer, vaginal cancer, small bowel cancer, bladder cancer, colorectal cancer, head and neck cancer, breast sarcoma, salivary gland cancer, ampullary cancer, skin cancer, non-melanoma, cancer of unknown primary, ovarian cancer, glioma, embryonal tumor, esophagogastric cancer, small cell lung cancer, appendiceal cancer, miscellaneous neuroepithelial tumor, non-small cell lung cancer, gastric cancer, melanoma, esophagogastric cancer, soft tissue sarcoma, thyroid cancer, prostate cancer, prostate cancer, or any combination thereof. In some embodiments, said cancer expresses a mutant in a p110 protein.

[0123] In some embodiments, said p110 protein is a p110p110 express the mutation in mutation in a In some embodiments, said mutation is a gain of function mutation. In some embodiments, said cancer has been previously determined as comprising a gain of amount, function, or signaling activity -type amount, function, or signaling activity In some embodiments, said mutation hotspot mutation. In some embodiments, the mutation is located at an amino acid at position10, 11, 12, 13, 38, 39, 71, 80, 81, 88, 90, 91, 93, 102, 103, 104, 105, 106, 107, 108, 109, 110,WSGR Ref: 64162-710.601 111, 112, 113, 114, 115, 118, 339, 344, 345, 350, 357, 364, 365, 378, 418, 419, 420, 421, 423, 436, 439, 444, 446, 447, 448, 449, 450, 451, 452, 453, 454, 455, 456, 457, 458, 464, 470, 471, 539, 542, 545, 546, 604, 726, 901, 939, 970, 1004, 1007, 1021, 1025, 1043, 1044, 1047, 1049, In some embodiments, said hotspot mutation comprises a H1047X mutation, a E542X mutation, a E545X mutation, or any combination thereof. In some embodiments, said hotspot mutation comprises a H1047R mutation, a E542K mutation, a E545K mutation, or any combination thereof. In some embodiments, said hotspot mutation comprises a mutation listed in Table 1. j. Identification of the mutation of the gene (e.g., PIK3CA gene)

[0124] In some embodiments, the cancer has been determined (e.g., previously determined) tocomprise the mutation (e.g., of the PIK3CA gene). The presence of the mutation of the gene may be determined before administration of the composition. For example, the determination (e.g., previous identification) of the mutation may take place months, weeks, days, hours, or even minutes ahead of the administering of the composition (e.g., the composition comprising a p110 inhibitor). The determination of the presence of the mutation (e.g., gain of function mutation) in the gene (e.g., the PIK3CA gene) may be conducted in any appropriate manner, including, but not limited to, identification of a gene mutation by any one or more tests discussed herein.

[0125] In some embodiments, the cancer has been determined (e.g., previously determined) ascomprising an increased amount, function, or signaling activity of . The presence of the increased amount of function of may be determined before administration of the composition. For example, the identification of the increased amount of function of may take place months, weeks, days, hours, or even minutes ahead (i.e., previously identified) of the administering of the composition (e.g., the composition comprising a p110 inhibitor). Determination of the presence of the increased amount of or function of may beconducted in any appropriate manner, including, but not limited to, identification by of any one or more tests discussed herein.

[0126] The mutation (e.g., gain of function mutation or of a PIK3CA gene) may be any acceptabletype of mutation, such as, for example, a substitution mutation, an insertion mutation, a deletion mutation, or a combination thereof. Determination of whether the mutation of the PIK3CA gene may be used to determine whether a patient comprises an increased amount, function, or signaling activity of as compared to a wild-type amount, function, or signaling activity of . In some embodiments, the PIK3CA mutation is a substitutionWSGR Ref: 64162-710.601 mutation. In some embodiments, the PIK3CA mutation is an insertion mutation. In some embodiments, the PIK3CA mutation is a deletion mutation.

[0127] Determining if a tumor has a PIK3CA genetic mutation may include identifying PIK3CAmutations in DNA extracted from a tumor sample and / or in circulating tumor or tumor cell DNA. In some embodiments, the cancer is determined to comprise the mutation before administration of the p110 inhibitor (i.e., the cancer is previously determined as comprising the mutation).

[0128] Multiple tests may be employed to detect PIK3CA mutations. For example, tests may includesequencing of the tumor DNA using Sanger sequencing of PCR-amplified PIK3CA encoding regions or next-gen sequencing (NGS) of whole genome or captured / enriched PIK3CA encoding regions (e.g., through whole-exome sequencing, or sequencing of a targeted mutation panel that includes PIK3CA exons and introns).

[0129] Mutations may also be detected in RNA. Such RNA mutations may be detected using RNA-Seq or DNA approaches to sequence cDNA derived from RNA. Furthermore, mutations may be detected through targeted amplification of variants and sequenced by next-generation sequencing (NGS) or through array-based readout of genetic variants (e.g., using Illumina BeadArrays). Tumor DNA may be derived from biopsy samples or captured from indirect tumor sources, such as blood derived cell-free DNA.

[0130] Function and amount of p110 or may be determined through any acceptable method,including, for example, methods that measure the phosphorylation levels of knowndownstream p110 signaling components. Methods to quantify these modifications may include western blots, mass-spectrometry, protein binding arrays, or immunohistochemistry. Some examples of markers that may be used for measuring function and amounts of p110 or include, but are not limited to AKTpS473 (phosphorylation of serine amino acidposition 473 of protein AKT), GSK3 alpha / beta pS21 / pS9, GSK3 pS9, Tuberin p1462, or a combination thereof. k. Improving cancer treatment efficacy

[0131] Methods provided herein may be useful in treating a cancer, such as, for example, byincreasing cancer cell proliferation, or killing of cancer cells.

[0132] inhibitor increases cancer cell inhibition. In some embodiments, the administering of a mutant increases cancer cell inhibition as compared to aWSGR Ref: 64162-710.601 different treatment. In some embodiments, the different treatment comprises a pan -p110inhibitor, a wildtype selective inhibitor, a p110 inhibitor, or a p110 inhibitor. In someembodiments, administering of a increases cancer cell inhibition in a cancer comprising a gain of function mutation of a PIK3CA gene compared to a corresponding administration of said to a second cancer that does not have a gain of function mutation of a PIK3CA gene. In some embodiments, administering of a increases cancer cell inhibition in a cancer comprising an increased amount, function, or signaling activity of compared to a corresponding administration of said to a second cancer that does not have an increased amount, function, or signaling activity of . l. Administration

[0133] Administration of the composition comprising a p110 inhibitor may be accomplished by anyacceptable means, including, for example, by parenteral administration. Acceptable means of parenteral administration include, but are not limited to, subcutaneous administration, intramuscular administration, and intravenous administration. In some embodiments, the method comprises administering a p110 inhibitor (e.g., a inhibitor). In some embodiments, administering comprises administering the p110 inhibitor parenterally. In some embodiments, the method comprises administering a pharmaceutical composition comprising ap110 inhibitor (e.g., such as any of the pharmaceutical compositions provided herein).

[0134] In some embodiments, administering comprises administering the p110 inhibitor enterally.Acceptable means of enteral administration include, but are not limited to, oral administration, gastric administration, and rectal administration.

[0135] In some embodiments, administering occurs once daily. In some embodiments, administeringoccurs twice daily. In some embodiments, administering occurs three times daily. m. Pharmaceutical Compositions

[0136] The p110 inhibitor may be delivered in the form of a pharmaceutical composition. In someembodiments, the pharmaceutical composition comprises a first p110 inhibitor and a secondp110 inhibitor (e.g., STX-478 and GSK-2636771). The pharmaceutical composition may be useful in the treatment of a cancer, such as, for example, a cancer determined as comprising a gain of function mutation of a PIK3CA gene or a cancer determined as comprising an increased amount, function, or signaling activity of as compared to a wild-type amount,function, or signaling activity of .WSGR Ref: 64162-710.601

[0137] The compositions described herein may comprise any appropriate p110 inhibitor, such as, forexample, any of the p110 inhibitors described herein (e.g., and a inhibitor). In some embodiments, the p110 inhibitor is a stereoisomer, pharmaceutically acceptable salt, hydrate, or solvate of a p110 inhibitor described herein. In some embodiments, the pharmaceutical composition comprises a p110 inhibitor and a pharmaceutically acceptable carrier (e.g., one or more pharmaceutically acceptable carrier, two or more pharmaceutically acceptable carriers, three or more pharmaceutically acceptable carriers, etc.). The carrier(s) may be any acceptable or suitable described herein. In some embodiments, the pharmaceutical composition comprising a p110 inhibitor is administered in a method of treating a patient (e.g., comprising a PIK3CA gain of function mutation of PIK3CA).

[0138] In certain embodiments, the p110 inhibitor described herein is administered as a purechemical (i.e., not with an excipient). In some embodiments, the p110 inhibitor described herein is combined with a pharmaceutically suitable or acceptable carrier (which may also be referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier) selected on the basis of a chosen route of administration and standard pharmaceutical practice as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21stEd. Mack Pub. Co., Easton, PA (2005)).

[0139] In some embodiments, the pharmaceutical composition comprising a p110 inhibitor isformulated for oral administration. Suitable oral dosage forms include, but are not limited to, tablets, pills, sachets, or capsules.

[0140] In some embodiments, the pharmaceutical composition comprising a p110 inhibitor isformulated for administration by injection. In some instances, the injection formulation is an aqueous formulation. In some instances, the injection formulation is a non-aqueous formulation. In some instances, the injection formulation is an oil-based formulation, such as sesame oil, or the like.

[0141] The dose of the composition comprising a p110 inhibitor may differ depending upon thesubject or patient's condition. Such factors for consideration may include general health status, age, and other factors.

[0142] The pharmaceutical compositions described herein may be administered in any mannerappropriate for the treatment or prevention of the disease (e.g., cancer). An appropriate dose and a suitable duration and frequency of administration may be determined by factors related to the condition of the patient, such as the type and severity of the patient's disease, the ernatively, an appropriate dose and a suitableWSGR Ref: 64162-710.601 duration and frequency of administration may be determined by factors related to the composition, such as the particular form of the active ingredient, and the method of administration. In cases, the appropriate dose is determined by factors related to both the condition of the patient and the composition. In general, an appropriate dose and treatment regimen may provide the composition(s) in an amount sufficient to provide therapeutic and / or prophylactic benefit (e.g., an improved clinical outcome, such as more frequent complete or partial remissions, or longer disease-free and / or overall survival). Optimal doses are generally determined using experimental models and / or clinical trials.

[0143] inhibitor. In some embodiments, the composition has an improved cancer cell inhibition compared to a pharmaceutical composition that comprises the mutant selective p embodiments, said cancer cell inhibition improves by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60% at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, at least about 100%, at least about 200%, at least about 300%, at least about 400%, or at least about 500%. In some embodiments, said cancer cell inhibition improves by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60% about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 97%, about 98%, about 99%, about 100%, about 200%, about 300%, about 400%, or about 500%.

[0144] -478, RLY-2608,RLY-5836, LY4045004, BPI-21668, LOXO-783, SNV-4818, inavolisib, or a combination -478. In -2608. In some -5836. In some embodiment -21668. In some-783. In some -4818. In some inavolisib. In someWSGR Ref: 64162-710.601 Formula (I) compound according to Formula (II) inhibitor comprises a compound according to Formula (IIIa). In some embodiments, said (IIIb). In some Formula (IIIc) compound according to Formula (IV). comprises AZD-6482, TGX-221, SAR-260301, KA-2237, AZD-8186, GSK-2636771, or a combination thereof. In some embodiments, said selective p -6482 -6482. In some-6482. In some embodiments, -221. In some embodiments, said selective - comprises KA-2237. In some embodiments, said selective p1 -ibitor comprises GSK-2636771. In some embodiments, said composition is a pharmaceutical composition. In some embodiments, the is a compound of Formula (V). In some embodiments, the selective is a compound of Formula (VI). inhibitor is a compound of Formula (VII). is a compound of Formula (VIII). II. Kits for Treating Cancer

[0145] Further provided herein, in some embodiments, are kits for treating a cancer, comprising: atest for determining: a gain of function mutation of a PIK3CA gene or an increased amount, function, or signaling activity of as compared to a wild-type amount, function, or signaling activity of ; and a phosphoinositide 3- p110 In someembodiments the mutation could comprise one of several possible hotspot mutations listed in Table 1. In some embodiments the test used to detect said mutation could be an NGS readout of a tumor tissue or liquid biopsy, for example by sequencing blood plasma derived circulating tumor DNA. inhibitor and a inhibitor. comprises STX-478, RLY-2608, RLY-5836, LY4045004, BPI-21668, LOXO-783, SNV- 4818, inavolisib, inhibitor comprises STX- comprises RLY-2608.WSGR Ref: 64162-710.601 RLY- - 21668. -783. In -4818. In some inavolisib. In some Formula I. In inhibitor comprises a compound according to Formula III. In some embodiments, said mutant selective p110 In someembodiments, said inhibitor is GSK-2636771, AZD-6482, AZD-8186, KA-2237, SAR- 260301, or a combination thereof. In some embodiments, said inhibitor is AZD-8186. In some embodiments, said inhibitor is a selective inhibitor. In some embodiments, said selective inhibitor is GSK-2636771, AZD-6482, AZD-8186, KA- 2237, or SAR-260301. In some embodiments, said selective inhibitor is GSK-2636771. In some embodiments, said selective inhibitor is AZD-6482. In some embodiments, said selective inhibitor is SAR-260301. In some embodiments, said selective inhibitor is AZD-8186. In some embodiments, said selective inhibitor is KA-2237. In some embodim is a compound of Formula (V). In someis a compound of Formula (VI). In some is a compound of Formula (VII). In some is a compound of Formula (VIII).

[0146] In some embodiments, said cancer comprises breast cancer, urothelial cancer, rectal cancer,thymus cancer, sarcoma, or a combination thereof. In some embodiments, said urothelial cancer comprises bladder cancer. hotspot mutation. In some embodiments, said hotspot mutation comprises a H1047X mutation, a E542X mutation, a E545X mutation, or any combination thereof. In some embodiments, said hotspot mutation comprises a H1047R mutation, a E542K mutation, a E545K mutation, or any combination thereof. comprises a hotspot mutation listed in Table 1. Definitions

[0147] As used in the specification and appended claims, unless specified to the contrary, thefollowing terms have the meaning indicated below.WSGR Ref: 64162-710.601

[0148] The singular forms (e.g., "a," "and" and "the") include plural referents unless the contextclearly dictates otherwise. Thus, for example, reference to "an agent" includes a plurality of such agents, and reference to "the cell" includes reference to one or more cells (or to a plurality of cells) and equivalents thereof known to those skilled in the art, and so forth. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all combinations and sub-combinations of ranges and specific embodiments therein are intended to be included.

[0149] The term "about" when referring to a number or a numerical range means that the number ornumerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range, in some instances, thestated value or range, and includes more specifically values of ±10%, ±5%, ±2%, and ±1% of the stated value or range.

[0150] activity or function associated with a disease means that the disease is caused by (in whole or in part), a symptom of the disease is caused by (in whole or in part) the substance or substance activity or function, or a side-effect of the compound (e.g., toxicity) is caused by (in whole or in part) the substance or substance activity or function.

[0151] The term "comprising" (and related terms such as "comprise" or "comprises" or "having" or"including") is not intended to exclude that in other certain embodiments, for example, an embodiment of any composition of matter, composition, method, or process, o r the like,described herein, "consist of" or "consist essentially of" the described features.

[0152] capable of being treated with the compounds or methods provided herein. In some embodiments, the disease as used herein refers to cancer.

[0153] reference to a protein-inhibitor interaction, means negatively affecting (e.g., decreasing) the activity or function of the protein (e.g., p110) relative to the activity or function of the protein in the absence of the inhibitor. The protein may be p110, such as, for example, . Thus, inhibition includes, at least in part, partially or totally blocking stimulation, decreasing, preventing, or delaying activation, or inactivating, desensitizing, or down-regulating signal transduction or enzymatic activity or the amount of a protein. Inhibition, and such terms, may refer to reduction of a disease or symptoms of disease when referred to in such context.

[0154] The compounds disclosed herein, in some embodiments, contain one or more asymmetriccenters and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms thatWSGR Ref: 64162-710.601 are defined, in terms of absolute stereochemistry, as (R)- or (S)-. Unless stated otherwise, it is intended that all stereoisomeric forms of the compounds disclosed herein are contemplated by this disclosure. When the compounds described herein contain alkene double bonds, and unless specified otherwise, it is intended that this disclosure includes both E and Z geometric isomers (e.g., cis or trans.) Likewise, all possible isomers, as well as their racemic andoptically pure forms, and all tautomeric forms are also intended to be included. The term Eor Z geometric isomers (e.g., cis or trans) of an alkene doubleortho-, meta-, and para- isomers around a benzene ring.

[0155] stabilize, and / or postpone development of the disease (such as cancer). This delay can be of varying lengths of time, depending on the history of the disease and / or individual being treated. As is evident to one skilled in the art, a sufficient or significant delay can, in effect, encompass prevention, in that the individual does not develop the disease. For example, a late stage cancer, such as development of metastasis, may be delayed.

[0156] ability to discriminate between molecular targets, such as inhibition, to a particular molecular target (e.g., ). For example, a selective inhibitor may have at least a 3x higher selectivity for the isoform compared to one of the other isoforms of p110 (e.g., , ,or p110 ) in a cell.

[0157] As used herein, compounds providing inhibitory properties (e.g., a p110 inhibitor), includesmall-molecule compounds and biological products (e.g., such as those derived from living material (e.g., antibodies, proteins, peptide fragments, etc), unless context clearly dictates otherwise.

[0158] A "tautomer" refers to a molecule wherein a proton shift from one atom of a molecule toanother atom of the same molecule is possible. The compounds presented herein, in certain embodiments, exist as tautomers. In circumstances where tautomerization is possible, a chemical equilibrium of the tautomers will exist. The exact ratio of the tautomers depends on several factors, including physical state, temperature, solvent, and pH. Some examples of tautomeric equilibrium include:WSGR Ref: 64162-710.601

[0159] "Pharmaceutically acceptable salt" includes both acid and base addition salts. Apharmaceutically acceptable salt of any one of the p110 inhibitors described herein is intended to encompass any and all pharmaceutically suitable salt forms. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0160] "Pharmaceutically acceptable acid addition salt" refers to those salts which retain thebiological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like. Also included are salts that are formed with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and. aromatic sulfonic acids, etc. and include, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Exemplary salts thus include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinate suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like. Also contemplated are salts of amino acids, such as arginates, gluconates, and galacturonates (see, for example, Berge S.M. et al.,WSGR Ref: 64162-710.601 "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66:1-19 (1997)). Acid addition salts of basic compounds are, in some embodiments, prepared by contacting the free base forms with a sufficient amount of the desired acid to produce the salt according to methods and techniques with which a skilled artisan is familiar.

[0161] "Pharmaceutically acceptable base addition salt" refers to those salts that retain the biologicaleffectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Pharmaceutically acceptable base addition salts are, in some embodiments, formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N- dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, N-methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. See Berge et al., supra.

[0162] "Pharmaceutically acceptable solvate" refers to a composition of matter that is the solventaddition form. In some embodiments, solvates contain either stoichiometric or non -stoichiometric amounts of a solvent, and are formed during the process of making with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of compounds described herein are conveniently prepared or formed during the processes described herein. The compounds provided herein exist in either unsolvated or solvated forms.

[0163] include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. In one aspect, the mammal is a human.

[0164] a change in a polynucleotide sequence that results ina change to protein function, amount of signaling, or protein levels. A change to proteinWSGR Ref: 64162-710.601 function may occur through a change to the protein encoded by the polynucleotide sequence. The change in function of the protein may be altered through an amino acid sequence of the protein or by a change in the amount (e.g., in an expression level), a change in how protein levels are regulated, including its expression, localization, and clearance / degradation.Mutations can be nucleotide substitutions, such as single nucleotide substitutions, insertions, or deletions, and may end up altering the splicing of messenger RNA (mRNA), the levels of mRNA, and / or the amino acid sequence of the protein encoded by said mRNA. A mutation can also be a change in the number of genomic copies of the gene (i.e. copy number variation). For example, a H1047R, E542K, or E545K mutation of PIK3CA causes it to constitutively signal through the p110 signaling pathway.

[0165] interchangeably. These terms refer to an approach for obtaining beneficial or desired results, including, but not limited to, a therapeutic benefit and / or a prophylactic benefit. The term disorder being treated. Also, a therapeutic benefit may be achieved with the eradication or amelioration of one or more of the symptoms associated with the underlying disorder such that an improvement may be observed in the patient, notwithstanding that the patient may still afflicted with the underlying disorder. For achieving a prophylactic benefit, the compositions may be administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease has not been made.

[0166] compound having the ability to inhibit a biological function (e.g., activity, expression, binding, protein-protein interaction) of a target protein. Accordingly, the t preferred inhibitors herein specifically interact with (e.g., bind to) the target, also included are degraders that inhibit a biological activity of the target protein by inducing destruction of the protein through ubiquitin and proteasome mechanisms. In particular, in some instances, degraders change the conformation of the protein which leads to its degradation through recruitment and activation of the proteosome complex. In some instances, degraders areproteolysis-targeting chimeric (PROTAC) protein degrader compounds. In some instances, degraders are chaperone-mediated protein degradation (CHAMP) protein degrader compounds.WSGR Ref: 64162-710.601 EXAMPLES

[0167] While preferred embodiments of the present disclosure 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 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. Example 1 Identification of Mutations in gene

[0168] Experiments were run in order to identify potential mutations in . Genomic DNA wasextracted from FFPE-preserved tumor biopsy tissue. Targeted capture was used to enrich for the exome, including all coding exons of all PIK3CA isoforms. NGS libraries were constructed and indexed using Illumina TruSeq exome kits (cat number 20020614) and then sequenced on an Illumina HiSeq platform. Somatic mutations were then called (e.g., per methods described in PMID 24192750 or PMID 33106175). Genome variants (SNVs and indels) were identified using GATK (PMID 20644199), and somatic mutations were called using Mutect2 (PMID 23396013) and Varscan (PMID 19542151). Loss of function mutations were identified on the basis of causing amino acid substitutions or protein coding changes with a predicted functional effect inferred by MutationTaster (PMID 20676075), a inferred by Polyphen-2 (PMID 23315928). Loss of function (LOF) mutations were filtered from likely gain of function (GOF) variants based on the absence of hotspot variants in LOF mutations. For example, LOF mutations may be identified as those that do not result, for example, in substitutions / deletions / alterations among the commonly altered amino acids. Gain of function (GOF) mutations were identified as known hotspot variants (e.g. H1047R, E542K, E545K; Table 1).

[0169] Deletions and amplifications (e.g., which may include a complete (zero copy) loss of one ormore regions of PIK3CA that overlap a portion of a coding exon or an entire coding exon, or an amplification of a region containing the entire PIK3CA gene) may also constitute PIK3CAmutations. Deletions and amplifications were called from whole exome NGS data or WGS (including low-pass) NGS data, using Control-FREEC (PMID 22155870). Western analysis and immunohistochemistry on FFPE preserved tumor biopsy was used to confirm a reduction or increase of PIK3CA gene expression at the protein level.WSGR Ref: 64162-710.601 Example 2 - A Study of p110 Inhibitors for the Treatment of Tumors Harboring Mutations

[0170] To determine the effects of p110 inhibitors in tumor cells harboring PIK3CA mutations, celllines with engineered PIK3CA were created and administered multiple p110 inhibitors. In particular, an engineered line comprising a PIK3CA loss of function (LOF) mutant was compared to its parental line (PIK3CA wild type), and a cell line with PIK3CB knocked out. Various p110 inhibitors were administered to each cell line.

[0171] To create cells with a loss of function PIK3CA mutation (PIK3CA-LOF mutant), the PIK3CAgene was knocked out in KP4 cells using CRISPR genome editing (kits sold by Synthego). The parental line of KP4 cells comprising PIK3CA wild type was used as a comparator, and KP4 cells with PIK3CB knocked out were used as a control. A cell viability assay was performed by treating the three isogenic lines with various concentrations of three different p110 inhibitors: GSK-2636771, a selective p -8186, a pand seletalisib, a selective p

[0172] As shown in FIGs. 1A-1C, cells having a PIK3CA LOF mutation exhibited increasedsensitivity to p110 inhibitors, such as GSK-2636771 and AZD-8186. However, no sucheffect was observed with seletalisib, a p110 inhibitor. FIG. 1A demonstrates favorableincreases in cancer cell inhibition when AZD-8186, a p110 inhibitor that potently inhibits p110 and p110 , is administered to KP4 cells comprising a PIK3CA LOF mutation,compared to administration of AZD-8186 in KP4 cells comprising PIK3CA wild type or PIK3CB LOF. LOF of PIK3CA confered an increased sensitivity to pharmacologic PI3K inhibition. FIG.1B demonstrates favorable increases in cancer cell inhibition when GSK- 2636771, a selective p110 inhibitor, is administered to KP4 cells comprising a PIK3CA LOFmutation, compared administration of GSK-2636771 to KP4 cells comprising PIK3CA wild type or PIK3CB LOF. LOF of PIK3CA confered an increased sensitivity to pharmacologic PI3K inhibition. FIG. 1C demonstrates no improvement in cancer cell inhibition whenseletalisib, a potent and selective p110 inhibitor, is administered to KP4 cells comprising aPIK3CA LOF mutation when compared to an administration of seletalisib to KP4 cells comprising PIK3CA wild type or PIK3CB LOF, demonstrating that the pharmacological sensitivity is caused by p11 inhibition, and not inhibition.

[0173] The results of this experiment demonstrate that there is synthetic lethality between p110inhibitors and a PIK3CA loss of function mutation; however, no synthetic lethality exists between p110 inhibitors and a PIK3CA loss of function mutation. The results alsodemonstrate that it is not the pharmacologic inhibition of PI3K that is responsible toincreased sensitivity induced by PIK3CA LOF and that inhibitors with p110 inhibition thatWSGR Ref: 64162-710.601 also inhibit other p110 variants (e.g., AZD-8186), may be useful in treating patients with a cancer comprising a PIK3CA LOF mutation. Example 3 - A Study of p110 Inhibitors for the Treatment of Tumors Harboring Mutations

[0174] The characterized cell lines, MDA-MB-231 and MDA-MB-453 were used in theseexperiments. MDA-MB-231 cells are a cancer cell line that are wildtype for all copies of . MDA-MB-453 cells are a cancer cell line that contain a H1047R mutation. A cell viability assay was performed by treating the cells with various concentrations of different and p110 inhibitors. The inhibitors used were t selective inhibitors inavolisib, STX- 478, RLY-2608. The p inhibitors -selective inhibitors GSK-2636771,TGX-221, and AZD-8186 a p inhibitor. Additionally, the general / non-mutant selectivealpelisib was tested.

[0175] Broadly, (GOF) mutant cell line MDA-MB-453 -type(wildtype) cell line MDA-MB-231 treated with 3x- mutant selective, 3x- -selective inhibitor, and as a-selective with 3x- mutant selective.The difference in sensitivity between the GOF mutant and wildtype cell lines was assessed by taking the ratio of IC50concentrations.

[0176] MDA-MB-453 and MDA-MB-231 cells were treated with 3x-fold titrated concentrations ofmutant selective inhibitor inavolisib alone (FIG.2A), 3x-fold titrated concentrations -selective inhibitor TGX-221 alone (FIG. 2B), and as a combination 1.85 µ -selective inhibitor TGX-221 with 3x- mutant selectiveinhibitor inavolisib (FIG.2C). The difference in sensitivity between the GOF mutant and wildtype cell lines was assessed by taking the ratio of IC50concentrations (FIG.2D). The mutant selective inhibitor had a difference in effect on inhibiting MDA-MB-453 cells versus MDA-MB-231 - selective inhibitor did not have a distinguished effect on either cell line. The combination of mutant selective -selective inhibitor had an unexpected synergistic effect specifically with MDA-MB-453 cells. These results demonstrate thatmutant selective -selective inhibitor would be mutated tumor cells while having a diminished effect on wildtype cells. These data demonstrate that the combination treatment induces a synergistic increase in growth inhibition in PIK3CA GOF mutant cells relative to PIK3CA WT cells.WSGR Ref: 64162-710.601

[0177] MDA-MB-453 and MDA-MB-231 cells were treated with 3x-fold titrated concentrations ofmutant selective inhibitor inavolisib alone (FIG.3A), 3x-fold titrated concentrations -selective inhibitor GSK-2636771 alone (FIG.3B), and as a combination 1.85 µM -selective inhibitor GSK-2636771 with 3x- mutantselective inhibitor inavolisib (FIG.3C). The difference in sensitivity between the GOF mutant and wildtype cell lines was assessed by taking the ratio of IC50concentrations (FIG.3D). The mutant selective inhibitor had a difference in effect on inhibiting MDA-MB-453 cells versus MDA-MB-231 - selective inhibitor did not have a distinguished effect on either cell line. The combination of mutant selective -selective inhibitor had an unexpected synergistic effect specifically with MDA-MB-453 cells. These results demonstrate that mutant selective -selective inhibitor would be mutated tumor cells while having a diminished effect on un-mutated cells.

[0178] MDA-MB-453 and MDA-MB-231 cells were treated with 3x-fold titrated concentrations ofmutant selective inhibitor STX-478 alone (FIG.4A), 3x-fold titrated concentrations -selective inhibitor AZD-8186 alone (FIG.4B), and as a combination 0.6 µM - selective inhibitor AZD-8186 with 3x- mutant selectiveinhibitor STX-478 (FIG.4C). The difference in sensitivity between the GOF mutant and wildtype cell lines was assessed by taking the ratio of IC50concentrations (FIG.4D). The mutant selective inhibitor had a difference in effect on inhibiting MDA-MB-453 cells versus MDA-MB-231 - selective inhibitor did not have a distinguished effect on either cell line. The combination of mutant selective -selective inhibitor had an unexpected synergistic effect specifically with MDA-MB-453 cells. These results demonstrate that mutant selective -selective inhibitor would be mutated tumor cells while having a diminished effect on un-mutated cells. These data also demonstrate that the combination treatment induces a synergistic increase in growth inhibition in PIK3CA GOF mutant cells relative to PIK3CA WT cells.

[0179] T47D and MDA-MB-231 cells were treated with 3x-mutant selective inhibitor STX-478 alone (FIG. 5A), 3x- -selective inhibitor AZD-8186 alone (FIG. 5B -selectiveinhibitor AZD-8186 with 3x- mutant selective inhibitorSTX-478 (FIG.5C). The difference in sensitivity between the GOF mutant and wildtype cellWSGR Ref: 64162-710.601 lines was assessed by taking the ratio of IC50concentrations (FIG.5D). The results mutant selective inhibitor had a difference in effect on inhibitingMDA-MB-453 cells versus MDA-MB-231 -selective mutant selective -selective inhibitor had an unexpected synergistic effect specifically with MDA-MB-453 cells. These results demonstrate that treatment with the mutant selective -selective inhibitor would be advantageous for while having a diminished effect on un-mutated cells. These data also demonstrate that the combination treatment induces a synergistic increase in growth inhibition in PIK3CA GOF mutant cells relative to PIK3CA WT cells.

[0180] MDA-MB-453 and MDA-MB-231 cells were treated with 3x-fold titrated concentrations ofmutant selective inhibitor STX-478 alone (FIG.6A), 3x-fold titrated concentrations -selective inhibitor GSK-2636771 alone (FIG.6B), and as a combination 0.023 µM mutant selective inhibitor STX-478 with 3x- inhibitor GSK-2636771 (FIG.6C). The difference in sensitivity between the GOF mutant and wildtype cell lines was assessed by taking the ratio of IC50concentrations (FIG.6D). The mutant selective inhibitor had a difference in effect on inhibiting MDA-MB-453 cells versus MDA-MB-231 - selective inhibitor did not have a distinguished effect on either cell line. The combination of mutant selective -selective inhibitor had an unexpected synergistic effect specifically with MDA-MB-453 cells. These results demonstrate that mutant selective -selective inhibitor would be mutated tumor cells while having a diminished effect on un-mutated cells. These data also demonstrate that the combination treatment induces a synergistic increase in growth inhibition in PIK3CA GOF mutant cells relative to PIK3CA WT cells.

[0181] MDA-MB-453 and MDA-MB-231 cells were treated with 3x-fold titrated concentrations ofmutant selective inhibitor RLY-2608 alone (FIG.7A), 3x-fold titrated concentrations -selective inhibitor TGX-221 alone (FIG. 7B), and as a combination 1.85 µM -selective inhibitor TGX-221 with 3x- mutant selectiveinhibitor RLY-2608 (FIG.7C). The difference in sensitivity between the GOF mutant and wildtype cell lines was assessed by taking the ratio of IC50concentrations (FIG.7D). The mutant selective inhibitor had a difference in effect oninhibiting MDA-MB-453 cells versus MDA-MB-231 -WSGR Ref: 64162-710.601 selective inhibitor did not have a distinguished effect on either cell line. The combination of mutant selective -selective inhibitor had an unexpected synergistic effect specifically with MDA-MB-453 cells. These results demonstrate that mutant selective -selective inhibitor would be mutated tumor cells while having a diminished effect on un-mutated cells. These data also demonstrate that the combination treatment induces a synergistic increase in growth inhibition in PIK3CA GOF mutant cells relative to PIK3CA WT cells.

[0182] MDA-MB-453 and MDA-MB-231 cells were treated with a combination of a low dose of-478 and a 3x- -selective inhibitorAZD-8186 (FIG. 8A -selective inhibitor AZD-8186 and a 3x- -478 (FIG. 8B). Themutant selective -selective inhibitor combination treatment had a difference in effect on inhibiting MDA-MB-453 cells versus MDA-MB-231 cells. The results also showed that the effect was not strongly distinguished mutant selective - selective -selective inhibitor and mutant selective inhibitor. Overall, these results are in line with

[0183] MDA-MB-453 and MDA-MB-231 cells were treated with a combination of a low dose of-478 and a 3x- -selective inhibitorGSK-2636771 (FIG.9 mutant selective inhibitor and-selective inhibitor combination treatment had a difference in effect on inhibiting MDA- MB-453 cells versus MDA-MB-231 cells. Overall, these results are in line with previously demonstrated data showing the combination treatment preferentia

[0184] MDA-MB-453 and MDA-MB-231 cells were treated with 3x-fold titrated concentrations ofthe general / non-mutant selective (i.e., inhibits both mutant + wildtype alpelisib alone (FIG. 10A), 3x- -selective inhibitor GSK-2636771 alone (FIG. 10B -selective inhibitor GSK-2636771 with 3x- alpelisib (FIG. 10C).The difference in sensitivity between the GOF mutant and wildtype cell lines was assessed by taking the ratio of IC50 concentrations (FIG. 10D). The results showed some distinction ininhibition between MDA-MB-453 cells versus MDA-MB-231 cells, which is expected asWSGR Ref: 64162-710.601 alpelisib -selective inhibitor did not have a distinguished effect on either cell line. Interestingly, there was not a strong change in -selective inhibitor mutant selective inhibitor -selective inhibitor synergistic effects. These results further demonstrate that the synergistic effect is unexpected and requires a gain of function mutation of a PIK3CA gene. These data also demonstrate that a non-mutant selective PI3K inhibitor, in combination witha PI3K inhibitor, does not recapitulate the synergies observed with mutant selective alphainhibitors.

[0185] MDA-MB-453 and MDA-MB-231 cells were treated with 3x-fold titrated concentrations ofthe general / non-mutant selective (i.e. inhibits both mutant + wildtype alpelisib alone (FIG.11A), 3x- -selective inhibitor TGX-221alone (FIG. 11B -selective inhibitor TGX-221 with 3x-alpelisib (FIG.11C). The difference in sensitivity between the GOF mutant and wildtype cell lines was assessed by taking the ratio of IC50concentrations (FIG.11D). The results showed some distinction in inhibition between MDA-MB-453 cells versus MDA-MB-231 cells, which is expected as alpelisib can inhibit -selective inhibitor did not have a distinguished effect on either cell line. Interestingly, there was not a strong change in inhibition seen the combination general -selective inhibitor treatment. This is a contrast to the data s mutant selective -selective inhibitor synergistic effects. These results further demonstrate that the synergistic effect is unexpected and requires a gain of function mutation of a PIK3CA gene. These data reinforce that a non- mutant selective PI3K inhibitor, in combination with a PI3K inhibitor, does not recapitulatethe synergies observed with mutant selective alpha inhibitors.Cells with and without a gain of function (GOF) mutation of a PIK3CA gene, MDA-MB-453 cells having and MDA-MB-231 cells ( ), respectively,were treated with 3x-fold titrated concentrations of inavolisib, a inhibitor, alone (FIG.15A); AZD-6482, a -selective inhibitor, alone (FIG.15B); or, a combination of inavolisib AZD-6482 -selective inhibitor (FIG.15C). A bar graph demonstrating the difference in sensitivity between the PIK3CA GOF mutant and PIK3CA wildtype cell lines through a ratio of IC50concentrations is shown in FIG.15D. These data demonstrate that the combination treatmentWSGR Ref: 64162-710.601 induces a synergistic increase in growth inhibition in PIK3CA GOF mutant cells relative to PIK3CA WT cells.

[0186] mutant selective inhibitor-selective inhibitor had an unexpected synergistic effect in cells harboring a - selective mutant selective -selective inhibitor combination. This provides an advantage of mutant selective -selective inhibitors in patient sub- populations identified as comprising a gain of function mutation of a PIK3CA gene. The data suggest that the mutant selective inhibitor induces synthetic lethality in combination PIK3CA GOF) cells. The synergy observed in this combined treatment of the mutant selective alpha inhibitor and beta inhibitor is enriched among PIK3CA GOF mutant cells, with a significantly smaller effect on wildtype cells. mutant selective inhibitor disproportionally affects MDA-MB-453 -MB-231) and the-selective inhibitors. It stands to reason that clinical application of the combination of therapies would be a synergistic boost in efficacy with minimal (i.e. non-synergistic) effects on toxicity. Furthermore, due to the lower IC50seen in the -selective inhibitor combinations and would thereby diminish off-target effects and physiological side effects. Example 5 Isogenically

[0187] inhibitor inhibitors on cells with a PIK3CA GOF mutation, cells with and without PIK3CA GOF mutations were treated with each inhibitor alone, and in combination.

[0188] Isogenic pairs of cell lines differing only in their PIK3CA mutation status (with and withoutPIK3CA gain of function mutation) were generated. Specifically, human PIK3CA (E545K / -) DLD-1 Cell Line from Accegen were isogentically paired: E545K mutant parental and KO of the E545K mutant allele. Synthego CRISPR Gene Knockout v2 kits were used to selectivelydisrupt / knock-out the PIK3CA GOF alleles in cells where PIK3CA is wildtype and present in 2 copies, but also present as a GOF mutation on additional copies.

[0189] Viability was assessed across a serially diluted range of drug concentrations, both alone, andmatrixed in combination. Synergy was detected in the combination of drugs as % inhibitionWSGR Ref: 64162-710.601 relative to no drug and background controls in the PIK3CA GOF mutant background, and compared with identical conditions in the wildtype background.

[0190] The results, as shown in FIGs. 12A-12D, demonstrate that a GOF E545K PIK3CA mutationis a cause of synergy between mutant-selective PI3K alpha inhibitor, inavolisib, and PI3K inhibitor, SAR260301. Furthermore, the results as shown in FIGs.12A-12H, demonstrate that mutant line shows greater synergistic effect with mutant selective PI3K alpha inhibitor, inavolisib, in combination with SAR260301, than non-mutant selective PI3K alpha inhibitor, alpelisib in combination with SAR260301. These results further demonstrate an advantage of -selective inhibitors in patient sub- populations identified as comprising a GOF mutation of a PIK3CA gene. Example 6 Viability of three different cell lines after treatment with various combinations of Inavolisib and SAR260301

[0191] Viability of three different cell lines after treatment with various combinations of inavolisiband SAR260301. The cell lines are: SKOV3 - H1047R PIK3CA, a mutant ovarian cell line (FIGs. 13A and 13B); MDA-MB-453- H1047R PIK3CA, a mutant breast cell line (FIGs.13C and 13D); and MDA-MB-231 - WT PIK3CA, breast cell line (negative control; FIGs. 13E and 13F). Synergy was assessed relative to expected additive effects on viability calculated from the drugs titrated as monotherapies.

[0192] As shown in FIGs. 13A-13F, synergy was observed across a range of combined mutantselective PI3K alpha inhibitor (Ianvolisib) and PI3K inhibitor (SAR260301) concentrationsand was beneficial on PIK3CA GOF mutations, consistent with the results in the prior examples. Example 7 Xenograft Study Using Cell Derived Xenograft Models

[0193] MDA-MB-453 cells havingmice to establish cell line-derived xenograft (CDX) tumors. After 5 weeks, mice were divided inavolisib or a combination of 5 mg / kg inavolisib and 30 mg / kg twice weekly and plotted as mean ± SEM. As shown in FIG. 14A, the mice treated with thecombination of inavolisib and GSK-2636771 exhibited significantly greater tumor growthinhibition as compared to other groups.

[0194] MDA-MB-453 cells having were subcutaneously injected into NSGmice to establish CDX tumors. After 7 weeks, mice were divided into six groups and treated inavolisib SAR260301SAR260301WSGR Ref: 64162-710.601 inavolisib and 20 mg / kg QD SAR260301 or a combination of 5 mg / kg inavolisib and 10 mg / kg BID SAR260301 measured twice weekly and plotted as mean ± SEM. As shown in FIG. 14B, the mice treatedwith the combination of inavolisib and SAR260301exhibited significantly greater tumor growth inhibition as compared to other groups.

[0195] Dosing (day 1) began once tumors reached palpable mass. Animals were dosed once a day byoral gavage and tumor sizes were measured with calipers. Tumor volume was calculated using the following formula: tumor volume (mm3) = 1 / 2 (W)2 x (L).

[0196] The results further demonstrate an-selective inhibitors in subject sub-populations expressing a GOF mutation of a PIK3CA gene. Example 8 Xenograft Study Using Cell Derived Xenograft Models

[0197] HCC1954 cells (from a breast cancer cell line) with a PIK3CA GOF mutation weresubcutaneously injected into NSG mice to establish cell line-derived xenograft (CDX) tumors. After 4 weeks, mice were divided into four groups and treated with vehicle (n mg / kg QD inavolisib (n ncombination of 2.5 mg / kg QD inavolisib and 80 mg / kg QD GSK2636771 (n oral gavage for 26 days. Tumor volumes were measured three times per week and plotted as mean ± SEM. Results of this study are shown in FIG.16. Example 9 Xenograft Study Using Patient Derived Xenograft Models

[0198] To investigate the potential for using p110 mutant selective and p110 inhibitors to treattumors with PIK3CA-GOF mutations, patient derived xenograft (PDX) models with measured GOF mutations in PIK3CA are identified from the NCI Patient Derived Model Repository (PDMR) and at Jackson Labs (JAX). The models contain H1047R mutations in PIK3CA as measured by NGS.

[0199] PDX harboring a PIK3CA GOF mutation, selected using the criteria described above, are cutto a uniform size and implanted subcutaneously into bilateral flanks of 5-week old NSG mice sourced from JAX. For each study (i.e. each model), multiple treatment arms, each consisting of 8 biological replicates, are included. Treatment arms include vehicle only control, mutant inhibitor monotherapy, selective inhibitor monotherapy, and several inhibitor combination therapies across various doses that are either the same or less than the monotherapy dose. Tumors are measured every other day until tumor volume reached approximately 150 mm3. BET inhibitor is administered (20 mg / kg) once daily by oral gavage. Tumor sizes are recorded daily, and body weights are measured every 7 days to monitor for drug toxicity. Tumor volume is calculated using theWSGR Ref: 64162-710.601 following formula: tumor volume (mm3) = 1 / 2 (W)2 x (L). Mice are sacrificed once tumors reached 1500 mm3. Differential outcomes are determined through a log rank Kaplan -Meiersurvival analysis or by comparing growth kinetics over time.

[0200] The examples and embodiments described herein are for illustrative purposes only and variousmodifications or changes suggested to persons skilled in the art are to be included within thespirit and purview of this application and scope of the appended claims.

Claims

1. WSGR Ref: 64162-710.601 CLAIMS What is claimed is:

1. A method of treating a cancer in a subject in need thereof, said method comprisingadministering a mutant selective subunit of phosphoinositide 3-kinase inhibitor - inhibitor is(STX-478), said p110 is not(AZD-6482),(SAR-260301), orWSGR Ref: 64162-710.601(GSK-2636771).

2. A method of treating a cancer in a subject in need thereof, said method comprisingadministering a mutant selective inhibitor and a p110 to said subject,wherein said administering exhibits a synergistic effect.

3. A method of treating a cancer in a subject in need thereof, said method comprisingadministering a mutant selective inhibitor and a p110 to said subject,wherein said administering improves an activity of inhibitor compared to acorresponding administration of the inhibitor without the p110 , or whereinsaid administering improves an activity of p110 compared to a correspondingadministration of the p110 without the inhibitor.

4. The method of claim 3, wherein said administering improves an activity of said mutantselective inhibitor compared to a corresponding administration of said inhibitor without said p110 .

5. The method of claim 3, wherein said administering improves an activity of said p110inhibitor compared to a corresponding administration of said p110 without saidmutant selective inhibitor.

6. The method of any one of claims 1 or 3 wherein said administering exhibits a synergisticeffect.

7. The method of claim 6, wherein said synergistic effect is on inhibiting tumor growth.

8. The method of claim 7, wherein said inhibition of tumor growth is exhibited for at least 4days.

9. The method of any one of the previous claims, wherein said administering inhibits tumorgrowth more than a corresponding administration of the mutant selective inhibitor without said p110 .

10. The method of claim 9, wherein said administering increases said cancer cell inhibitioncompared to a corresponding administering of the mutant selective inhibitor alone.

11. The method of claim 9, wherein said administering increases said cancer cell inhibitioncompared to a corresponding administering of the p110 without said mutantselective inhibitor.WSGR Ref: 64162-710.60112. The method of claim 11, wherein said administering increases said cancer cell inhibitioncompared to an administering of the p110 alone.

13. The method of any one of claims 7-12, wherein said cancer cell inhibition is increased by atleast 5%.

14. The method of claim 12, wherein said cancer cell inhibition is increased by at least 10%.

15. The method of claim 12, wherein said cancer cell inhibition is increased by at least 15%.

16. The method of claim 12, wherein said cancer cell inhibition is increased by at least 25%.

17. The method of claim 12, wherein said cancer cell inhibition is increased by at least 30%.

18. The method of claim 12, wherein said cancer cell inhibition is increased by at least 40%.

19. The method of claim 12, wherein said cancer cell inhibition is increased by at least 50%.

20. A method of treating a cancer in a subject in need thereof, said method comprisingadministering a p110 to said subject, wherein said subject has received or has beenpreviously determined to receive a mutant selective inhibitor.

21. The method of claim 20, wherein said method further comprises administering said mutantselective inhibitor to said subject.

22. The method of any one of claims 20 or 21, wherein said cancer was previously determinednot to respond to said mutant selective inhibitor.

23. The method of claim 22, wherein a tumor of said cancer was determined to increase in a sizeor increase in a rate of growth.

24. A method of treating a cancer in a subject in need thereof, said method comprisingadministering a mutant selective inhibitor and a p110 to said subject,wherein said cancer has been previously determined to not respond to said inhibitor.

25. The method of claim 24, wherein a tumor of said cancer was determined to increase in a sizeor increase in a rate of growth.

26. The method of any one of the previous claims, wherein said mutant selective inhibitorcomprises STX-478, RLY-2608, RLY-5836, LY4045004, BPI-21668, LOXO-783, SNV- 4818, inavolisib, or a combination thereof.

27. The method of any one of the previous claims, wherein said mutant selective inhibitorcomprises a compound according to Formula (I):WSGR Ref: 64162-710.601 Formula (I), or a pharmaceutically acceptable salt thereof, wherein: Z is O or NRx; Rxis hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl; each R1is independently selected from halogen, hydroxyl, cyano, C1-C6 alkyl optionally substituted with hydroxyl, and C3-C6 cycloalkyl; m is 0, 1, 2, or 3; R2is halogen, hydroxyl, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 haloalkyl, C3-C6 cycloalkyl optionally substituted with 1 or 2 fluoro; R3is a C1-C6 alkyl, a C1-C6 haloalkyl, or a C3-C6 cycloalkyl optionally substituted with 1 or 2 substituents independently selected from fluoro and C1-C6 alkyl; Ring A is a 6-10 membered aryl, a C3-C8 cycloalkyl, a 5-10 membered heteroaryl, or a 4-10 membered heterocyclyl; each R4is independently selected from the group consisting of: (i) halogen, (ii) C1-C6 alkyl optionally substituted with 1 or 2 hydroxyl or NRARB, (iii) C1-C6 alkoxy optionally substituted with 1-2 substituents independently selected from hydroxyl and C3-C6 cycloalkyl, (iv) C1-C6 haloalkyl, (v) hydroxyl, (vi) cyano, (vii) CO2H, (viii) NRARB, A2, (x)CRD, (xi) SO2(NRERF), (xii) SO2(C1-C6 alkyl), (xiii) -C6 alkyl), (xiv) -C6 alkyl), (xv) CO2(C1-C6 alkyl), (xvi) 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl, (xvii) 3-9 membered heterocyclyl optionally substituted with 1 or 2 independently selected RG, and (xviii) 3-6 membered cycloalkyl optionally substituted with 1 or 2 independently selected RG; n is 0, 1, or 2;WSGR Ref: 64162-710.601 each RA, RA1, RB, RB1, RC, RC1, RD, RD1, RE, and RFis independently (i) hydrogen, (ii) hydroxyl, (iii) 4-6 membered heterocyclyl, (iv) C1-C6 haloalkyl, (v) -C6 alkyl), (vi) -C6 alkyl), (vii) SO2(C1-C6 alkyl), (viii) 3-6 membered cycloalkyl optionally substituted with hydroxyl, or (ix) C1-C6 alkyl optionally substituted with 1-2 substituents independently selected from hydroxyl,B2RC2, 5-6 membered heteroaryl, 3-6 membered cycloalkyl, SO2(C1- C6 alkyl), CO2H, and SO2(NH2); or RCand RD, together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from hydroxyl, halogen,B1RC1, SO2(C1-C6 alkyl), CO2H, C1-C6 alkyl optionally substituted with hydroxyl, C1-C6 alkoxy, and C1-C6 haloalkoxy; each RA2, RB2, and RC2is independently hydrogen or C1-C6 alkyl; each RG is independently selected from the group consisting of: fluoro, cyano, hydroxyl, C1 -C6 alkyl optionally substituted with hydroxyl, C1-C6 alkoxy, NRA1RB1 A2, C1RD1, CO2(C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 haloalkoxy, SO2(C1-C6 alkyl), and CO2H.

28. The method of claim 27, wherein said mutant selective inhibitor comprises(STX-478).

29. The method of any one of the previous claims, wherein said mutant selective inhibitorcomprises a compound according to Formula (II):WSGR Ref: 64162-710.601Formula (II), or a pharmaceutically acceptable salt thereof, wherein: Eis C(O) , C(RE)2 , C(RE)2C(RE)2 , C(S) , S(O)2 , OC(O) ,N(RE)C(O) , C(O)N(RE) , or C(RE)2C(O) ;Q is CH, C(RQ), or N; X is CH, C(RX), or N; Y is CH, C(RY), or N; Z is CH, C(RZ), or N; R1is -L1-R1A; R2is -L2-R2A; each instance of REis independently H or -LE-REA. RQis -LQ-RQA; RXis -LX-RXA; RYis -LY-RYA; RZis -LZ-RZA; or two instances of REare taken together with their intervening atoms to form a 3-8 membered saturated or partially unsaturated monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8-12 membered saturated or partially unsaturated bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein each ring is substituted with n instances of REEC; RQand R1are taken together with their intervening atoms to form a 4-8 membered saturated or partially unsaturated monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8-12 membered saturated or partially unsaturated bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein each ring is substituted with p instances of RQ1C; RYand RZare taken together with their intervening atoms to form a 4-7 membered partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said ring is substituted with q instances of RYZC; each of L1, L2, LE, LQ, LX, LY, and LZis independently a covalent bond, or a C1-4bivalent saturated or unsaturated, straight or branched hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by CH(RL) ,WSGR Ref: 64162-710.601C(RL)2 , C3-6 cycloalkylene, C3-6 heterocycloalkylene, N(R) , N(R)C(O) ,N(R)C(NR) , N(R)C(NOR) , N(R)C(NCN) , C(O)N(R) , N(R)S(O)2 ,S(O)2N(R) , O , C(O) , OC(O) , C(O)O , S , S(O) , or S(O)2 ;R1Ais RAor RBsubstituted by r1instances of R1C; R2Ais RAor RBsubstituted by r2instances of R2C; REAis RAor RBsubstituted by r3instances of REC; RQAis RAor RBsubstituted by r4instances of RQC; RXAis RAor RBsubstituted by instances of RXC; RYAis RAor RBsubstituted by r6instances of RVC; RZAis RAor RBsubstituted by r7instances of RZC; RLis RAor RBsubstituted by r8instances of RLC; each instance of RAis independently oxo, deuterium, halogen, CN, NO2, OR, SF5, SR, NR2, S(O)2R, S(O)2NR2, S(O)2F, S(O)R, S(O)NR2, S(O)(NR)R, C(O)R, C(O)OR, C(O)NR2, C(O)N(R)OR, OC(O)R, OC(O)NR2, N(R)C(O)OR, N(R)C(O)R, N(R)C(O)NR2, N(R)C(NR)NR2, N(R)S(O)2NR2, N(R)S(O)2R, P(O)R2, P(O)(R)OR, or B(OR)2; each instance of RBis independently a C1-6aliphatic chain; phenyl; naphthyl; cubanyl; adamantyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each instance of R1C, R2C, REC, RQC, RXC, RYC, RZC, RLC, REEC, RQ1C, and RYZCis independently oxo, deuterium, halogen, CN, NO2, OR, SF5, SR, NR2, S(O)2R, S(O)2NR2, S(O)2F, S(O)R, S(O)NR2, S(O)(NR)R, C(O)R, C(O)OR, C(O)NR2, C(O)N(R)OR, OC(O)R, OC(O)NR2, N(R)C(O)OR, N(R)C(O)R, N(R)C(O)NR2, N(R)C(NR)NR2, N(R)S(O)2NR2, N(R)S(O)2R, P(O)R2, P(O)(R)OR, B(OR)2, or an optionally substituted group selected from C1-6aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, andWSGR Ref: 64162-710.601 sulfur, and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each instance of R is independently hydrogen, or an optionally substituted group selected from C1-6aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two R groups on the same nitrogen are taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur; andeach of n, p, q, r1, r2, r3, r4, r5, r6, r7, and r8is independently 0, 1, 2, 3, or 4.

30. The method of claim 29, wherein said mutant selective inhibitor comprises(RLY-2608).

31. The method of any one of the previous claims, wherein said mutant selective inhibitorcomprises a compound according to Formula (IV):Formula (IV), or pharmaceutically acceptable salts thereof, wherein: R1is selected from CH3, CH2CH3, CH(CH3)2, CHF2, CH2F, and CF3; X is selected from:WSGR Ref: 64162-710.601where the wavy line indicates the site of attachment; and R2is selected from H, C1-C6alkyl, cyclopropyl, and cyclobutyl, optionally substituted with F, OCH3, or OH.

32. The method of claim 31, wherein said mutant selective inhibitor comprises(inavolisib).

33. The method of any one of the previous claims, wherein said mutant selective inhibitorcomprises LOXO-783.

34. The method of any one of the previous claimscomprises a compound according to Formula (IIIa):Formula (IIIa), or pharmaceutically acceptable salts thereof, wherein:WSGR Ref: 64162-710.601R is H or C1-C3alkyl; R1is a group of the formula: R2is an optionally substituted bicyclic ring selected from 1,3-benzodioxole, 2,3-dihydro-1,4- benzodioxine, isoindolin-1-one, indolin-2-one, benzo[d]oxazol-2(3H)-one, 1,3-dihydro-2H- pyrrolo[2,3-b]pyridin-2-one, or 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine, or an optionally substituted bicyclic heteroaryl of 8 to 10 ring atoms containing 1, 2, 3, 4, or 5 ring heteroatoms independently selected from N, O, or S; wherein the optionally substituted bicyclic ring is optionally substituted with one to three substituents each independently selected from halogen and C1-C6alkyl; the optionally substituted bicyclic heteroaryl is optionally substituted with one to three substituents each independently selected from CN, halogen, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, SO2R10, C(O)OC1-C3alkyl, CONR10R10, NR10R10, NR10CO2R10, OH, an optionally substituted C1-C6alkyl, an optionally substituted C2-C6alkenyl, an optionally substituted C2-C6alkynyl, an optionally substituted C3-C5cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, an optionally substituted 1,3-benzodioxole, an optionally substituted 2,3-dihydro-1,4-benzodioxine, or anWSGR Ref: 64162-710.601 optionally substituted heteroaryl selected from pyridine, pyrimidine, pyridazine, pyrazine, pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optionally substituted C1-C6alkyl, C2-C6alkenyl, or C2-C6alkynyl is each optionally substituted with a CN, OH, oxetanyl, C1-C3alkoxy, CONR10R10, or phenyl; the optionally substituted C3-C5cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocycle or heteroaryl is each optionally substituted with one to three substituents each independently selected from halogen, C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, SO2R10, NR10R10, OH or CN; R3is H, halogen, CN, N(H)(C1-C3alkyl), N(C1-C3alkyl)2, N(H)(CH2CH2CO2H), C(O)C1-C3alkyl, C1-C6alkyl C1-C6haloalkyl, C1-C6hydroxyalkyl, C3-C5cycloalkyl, an optionally substituted heterocycle of 3 to 5 ring atoms containing 1, 2, or 3 ring heteroatoms independently selected from N, O, or S, or an optionally substituted heteroaryl of 5 or 6 ring atoms containing 1, 2, or 3 ring heteroatoms independently selected from N, O, or S; wherein the optionally substituted heterocycle or heteroaryl is each optionally substituted with one to three substituents each independently selected from halogen, C1-C3alkyl, or C1-C3haloalkyl; each of R4, R5and R6is independently H, halogen, C1-C6alkyl or C1-C6haloalkyl; R7is CN, C1-C6alkyl or C1-C6haloalkyl; R8is H or C1-C6alkyl; each R9is independently H, halogen, CN, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy or C3-C5cycloalkyl; and each R10is independently H or C1-C3alkyl.

35. The method of any one of the previous claims, wherein saidcomprises a compound according to Formula (IIIb):Formula (IIIb), or pharmaceutically acceptable salts thereof, wherein: R is H or C1-C3alkyl; R1is a group of the formula:WSGR Ref: 64162-710.601R3is H, halogen, CN, N(H)(C1-C3alkyl), N(C1-C3alkyl)2, N(H)(CH2CH2CO2H), C(O)C1-C3alkyl, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C3-C5cycloalkyl, an optionally substituted heterocycle of 3 to 5 ring atoms containing 1, 2, or 3 ring heteroatoms independently selected from N, O, or S, or an optionally substituted heteroaryl of 5 or 6 ring atoms containing 1, 2, or 3 ring heteroatoms independently selected from N, O, or S; wherein the optionally substituted heterocycle or heteroaryl is each optionally substituted with one to three substituents each independently selected from halogen, C1-C3alkyl, or C1-C3haloalkyl; each of R4, R5and R6is independently H, halogen, C1-C6alkyl or C1-C6haloalkyl; R7is CN, C1-C6alkyl or C1-C6haloalkyl; R8is H or C1-C6alkyl;WSGR Ref: 64162-710.601 each R9is independently H, halogen, CN, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, or C3-C5cycloalkyl; each R10is independently H, CN, halogen, C1-C6haloalkyl, C1-C6alkoxy, C1- C6haloalkoxy, SO2R11, C(O)OC1-C3alkyl, CONR11R11, NR11R11, NR11CO2R11, OH, an optionally substituted C1-C6alkyl, an optionally substituted C2-C6alkenyl, an optionally substituted C2-C6alkynyl, an optionally substituted C3-C5cycloalkyl, an optionally substituted heterocycle selected from pyrrolidine, pyrrolidinone, piperidine or morpholine, an optionally substituted phenyl, an optionally substituted 1,3-benzodioxole, an optionally substituted 2,3-dihydro-1,4-benzodioxine, or an optionally substituted heteroaryl selected from pyrazole, isoxazole, isothiazole, imidazole, oxazole, or thiazole; wherein the optionally substituted C1-C6alkyl, C2-C6alkenyl, or C2-C6alkynyl is each optionally substituted with a CN, OH, oxetanyl, C1-C3alkoxy, or CONR11R11; the optionally substituted C3-C5cycloalkyl, phenyl, 1,3-benzodioxole, 2,3-dihydro-1,4-benzodioxine, heterocycle or heteroaryl is each optionally substituted with one to three substituents each independently selected from halogen, C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, C1- C3haloalkoxy, SO2R11, NR11R11, OH or CN; and each R11is independently H or C1-C3alkyl.

36. The method of any one of the previous claims, wherein said mutant selective inhibitorcomprises a compound according to Formula (IIIc):or pharmaceutically acceptable salts thereof, wherein: Xis NR12 or O ;Y is C(R11)2 , O , NR11 , or S ;W is N , O , or S , wherein when W is O or S , R1 or R2 is absent;each R1and R2is independently H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1- C6haloalkyl, C1-C6alkoxy, (CH2)mR12, (CH2)mOR12, (CH2)mN(R12)2, (CH2)mC(O)R12, (CH2)mC(O)OR12, (CH2)mC(O)N(R12)2, C3-C10cycloalkyl, heterocycle, aryl, or heteroaryl, wherein the cycloalkyl, heterocycle, aryl, and heteroaryl areWSGR Ref: 64162-710.601 12, halogen, CN, NO2, C1-C6alkyl, C2- C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, (CH2)nOR12, (CH2)nN(R12)2, (CH2)nC(O)R12, (CH2)nC(O)OR12, (CH2)nC(O)N(R12)2, (CH2)nSO2R12, C3-C6cycloalkyl, aryl, heteroaryl, or R15; or R1and R2, together with the nitrogen to which they are attached, form a heterocycle comprising 1-4 heteroatoms selected from O, N, and S, wherein the heterocycle is optionally substituted with one or more R10; each R3, R4, R5, and R6is independently H, halogen, CN, C1-C6alkyl, C2-C6alkenyl, C2- C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, (CH2)mR12, (CH2)mOR12, (CH2)mN(R12)2, (CH2)mC(O)R12, (CH2)mC(O)OR12, (CH2)mC(O)N(R12)2, C3- C10cycloalkyl, aryl, heterocycle comprising 1-4 heteroatoms selected from O, N, and S, or heteroaryl comprising 1-4 heteroatoms selected from O, N, and S; each R7and R8is independently H, halogen, CN, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxy; R9 11, halogen, CN, NO2, C1-C6alkyl, C2- C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, (CH2)mN(R12)2, (CH2)mOR12, (CH2)m CR13(OH) R12, (CH2)m C(O)R12, (CH2)m C(O)OR12,(CH2)mC(O)N(R12)2, (CH2)mC(O)N(OH)R12, (CH2)mSO2R12, (CH2)mSO2OR12, (CH2)mSO2N(R12)2, (CH2)mP(O)(OR12)2, (CH2)mP(O)(R12)2, (CH2)mP(O)(OR13)R12, (CH2)mB(OH)2, (CH2)mB(R12)2, (CH2)mO(CH2CH2 O)rR13, (CH2)m NR12 (CH2CH2 O)rR13, (CH2)m C(O) (CH2CH2O)rR13, (CH2)m C(O)O (CH2CH2 O)rR13, (CH2)m C(O)NR12 (CH2CH2 O)rR13,(CH2)m C(O) NR12 SO2R13, (CH2)m SO2NR12 C(O)R13, (CH2)mS(O)(NR12) R13, C3-C10 cycloalkyl, aryl, heterocycle comprising 1-4 heteroatoms selectedfrom O, N, and S, or heteroaryl comprising 1-4 heteroatoms selected from N, O, and S, wherein the C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C3- C10cycloalkyl, aryl, heterocycle, or heteroaryl is optionally substituted with one or more oxo, halogen, CN, OH, NH2, NO2, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1- C6haloalkyl, or C1-C6alkoxy, or two R9, together with the atoms to which they are attached form a C3-C10cycloalkyl, an aryl, or a heterocycle comprising 1-4 heteroatoms selected from O, N, and S, wherein the cycloalkyl, aryl, or heterocycle is optionally substituted with one or more oxo, halogen, CN, OH, NH2NO2, C1-C6alkyl, C2-C6alkenyl, C2- C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxy; R10at each occurrence is independently oxo, halogen, CN, C1-C6alkyl, C2-C6alkenyl, C2- C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, (CH2)nOR12, (CH2)nN(R12)2, (CH2)nWSGR Ref: 64162-710.601 C(O)R12, (CH2)nC(O)OR12, (CH2)nC(O)N(R12)2, (CH2)nSO2R12, (CH2)nO (CH2CH2 O)rR13, C3-C10 cycloalkyl, heterocycle, (CH2)n-aryl, or heteroaryl, whereinthe cycloalkyl, heterocycle, aryl, and heteroaryl is optionally substituted with halogen, C 1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, (CH2)nSO2R12, (CH2)nC(O)R12, (CH2)nC(O)OR12, or (CH2)nC(O)N(R12)2, or two R10, together with the atoms to which they are attached, form a C3-C10cycloalkyl, an aryl, a heterocycle comprising 1-4 heteroatoms selected from O, N, and S, or a heteroaryl, wherein the cycloalkyl, aryl, heterocycle, and heteroaryl are optionally substituted with one 12, halogen, CN, NO2, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1- C6haloalkyl, C1-C6alkoxy, (CH2)nOR12, (CH2)nN(R12)2, (CH2)nC(O)R12, (CH2)nC(O)OR12, (CH2)nC(O)N(R12)2, (CH2)nSO2R12, C3-C6cycloalkyl, aryl, heteroaryl, or R15; R11is H, C1-C6alkyl, C2-C6alkenyl, or C2-C6alkynyl; each R12and R13at each occurrence is independently H, C1-C6alkyl, C2-C6alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, (CH2)q O C(O) (CH2)r R14, (CH2)qNH C(O) (CH2)r R14, (CH2)q O C(O) (CH2)r OR14, (CH2)q NH C(O)(CH2)r OR14, (CH2)q O (CH2)r R14, (CH2)q NH (CH2)r R14, (CH2)q O(CH2)r OR14, (CH2)q NH (CH2)r OR14, C3-C10 cycloalkyl, heterocycle comprising 1-4 heteroatoms selected from O, N, and S, (CH2)q-aryl, or heteroaryl comprising 1-4 heteroatoms selected from N, O, and S, wherein the cycloalkyl, heterocycle, aryl, and heteroaryl are optionally substituted with one or more halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, or C1-C6haloalkoxy; Ring A is C3-C10cycloalkyl, aryl, heterocycle comprising 1-4 heteroatoms selected from N, O, and S, or heteroaryl comprising 1-4 heteroatoms selected from N, O, and S; R14istwo R15, together with the atoms to which they are attached form a cycloalkyl, an aryl, a heterocycle comprising 1-4 heteroatoms selected from O, N, and S, or a heteroaryl, wherein the cycloalkyl, aryl, heterocycle, and heteroaryl are optionally substituted with one or more C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, (CH2)nOR12, (CH2)nN(R12)2, (CH2)nC(O)R12, (CH2)nC(O)OR12, (CH2)nC(O)N(R12)2, or (CH2)nSO2R12; andWSGR Ref: 64162-710.601 each n, m, q, r, or s is independently at each occurrence 0, 1, 2, 3, 4, 5, or 6;provided that when R1and R2together with the nitrogen atom to which they are attached form a morpholine and: i. when Y is O ; R3, R4, and R6 are hydrogen; R7 is methyl; X isNR12and Ring A is aryl; then R5is not C(O)N(R12)2or C(O)OR12; ii. when Y is O, or NR11 ; R3, R4, R6 and R8 are hydrogen; R7 is H or C1-C6 alkyl; X is NR12 andRing A is phenyl or pyridyl; then R5is not H, OH, OCH3, OCF3, F, Cl, CF3, C1-C6alkyl, or (CH2)m-aryl; or iii. when R5is CH3, then either (a) the morpholine is substituted or (b) Ring A is not phenyl.

37. The method of any one of the previous claims, wherein said mutant selective inhibitorcomprises SNV-4818.

38. The method of any one of the previous claims, wherein said p110 comprises aselective p110 .

39. The method of claim 38, wherein said selective p110 comprises AZD-6482, TGX-221, SAR-260301, KA-2237, AZD-8186, GSK-2636771, PIK-108, or a combination thereof .

40. The method of claim 39, wherein said selective p110 comprises(AZD-8186).

41. The method of claim 39, wherein said selective p110 comprises(AZD-6482).

42. The method of claim 39, wherein said selective p110 comprisesWSGR Ref: 64162-710.601(TGX-221).

43. The method of claim 39, wherein said selective p110 comprises(SAR-260301).

44. The method of claim 39(GSK-2636771).

45. The method of claim 39(PIK-108).

46. The method of claim 39 -2237.WSGR Ref: 64162-710.60147. The method of any one of the previous claims, wherein said administering increases a cancercell inhibition in a cancer cell comprising a mutation compared a cancer cell comprising wildtype .

48. The method of any one of the previous claims, wherein said cancer comprises endometrialcancer, breast cancer, cervical cancer, anal cancer, vaginal cancer, small bowel cancer, bladder cancer, colorectal cancer, head and neck cancer, small cell lung cancer, non-small cell lung cancer ovarian cancer, prostate cancer, gastric cancer, melanoma, esophogastric cancer, glioma, soft tissue sarcoma, thyroid cancer, prostate cancer, or any combination thereof.

49. The method of any one of the previous claims, wherein said cancer comprises a mutation in aPIK3CA gene.

50. The method of any one of the previous claims, wherein said cancer comprises a mutation in ap110 protein.

51. The method of claim 50, wherein said p110 protein is a p11052. The method of claim 49, wherein said cancer has been previously determined to express themutation in a protein.

53. The method of any one of the previous claims, wherein said administering increases cancercell inhibition.

54. The method of claim 53, wherein said administering increases said cancer cell inhibitioncompared to a corresponding administration to a cancer expressing a wildtype form of p110 alpha.

55. The method of any one of the previous claims, wherein said cancer expresses a mutation in a.

56. The method of claim 55, wherein said mutation of said comprises a hotspot mutation.

57. The method of claim 56, wherein said hotspot mutation comprises a H1047X mutation, aE542X mutation, a E545X mutation, or any combination thereof.

58. The method of claim 57, wherein said mutation in said comprises said H1047Xmutation.

59. The method of claim 57, wherein said mutation in of said comprises said E542Xmutation.

60. The method of claim 57, wherein said mutation in of said comprises said E545Xmutation.

61. The method of any one of claims 55-60, wherein said mutant is a gain of function mutant.

62. The method of any one of the previous claims, wherein said administering increases anactivity of said mutant selective inhibitor for at least 4 days.WSGR Ref: 64162-710.60163. The method of any one of the previous claims, wherein said cancer has been previouslydetermined as comprising a gain of function mutation of a gene.

64. The method of any one of the previous claims, wherein said cancer has an increased amount,function, or signaling activity of as compared to a wild-type amount, function, or signaling activity of .

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