Enantiomer of azo podophyllotoxin derivative SU056

Abstract

The invention relates to a preparation method of 9-(3-fluorophenyl)-5-(2-ethoxyl)-6, 9-dihydro-[1, 3] dioxacyclo [4, 5-g] furo [3, 2-b] pyridine. The present invention relates to novel enantiomers of [1, 2, 4-b] quinoline-8 (5H)-one (SU056) and pharmaceutically acceptable salts thereof, pharmaceutical compositions comprising said novel enantiomers and the use of said novel enantiomers in medical treatments, including in particular cancer treatments.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority under 35 U.S.C. §119(e) to U.S. Provisional Patent Application No. 63 / 388,537, filed on July 12, 2023, which is hereby incorporated by reference in its entirety. Technical Field

[0003] The present invention relates to a novel left-hand enantiomer of 9-(3-fluorophenyl)-5-(2-hydroxyethyl)-6,9-dihydro-[1,3]dioxetine[4,5-g]furo[3,4-b]quinolin-8(5H)-one (L-SU056) and the use of the novel enantiomer in medical treatment, particularly in cancer treatment. Background Art

[0004] Y-box binding protein 1 (YB-1, YBX1) is a multifunctional cold shock protein that binds to DNA and RNA and is associated with tumor progression and the emergence of therapy resistance (TR). It regulates DNA and RNA-related cellular events, including mRNA transcription, splicing, packaging, stability, and translation (Lyabin et al., 2014, YB-1 protein: functions and regulation. Wiley Interdiscip Rev RNA 5, 95-110). mRNA stabilization is an important event for the sustained expression of any gene, and YB-1 potently stabilizes mRNA by preventing mRNA degradation at the 5' end (Evdokimova et al., 2001, The major mRNA-associated protein YB-1 is a potent 5'cap-dependent mRNA stabilizer. European Molecular Biology Organization Journal (EMBO J), 20, 5491-502). It was originally described by Didier et al. as a negative regulator of MHC class II molecules (Didier et al., 1988). The oncogenic effect of YB-1 has been well characterized in many cancers, and its amplified levels have been found in a large number of cancer cases (Goodarzi et al., Cell 161, 790-802, 2015).It increases the stability of short-lived mRNAs of various oncogenic proteins, including c-myc (Laird-Offringa et al., 1990. Poly(A) tail shortening is the translation-dependent step in c-myc mRNA degradation. Mol Cell Biol, 10, 6132-40), c-fos (Blattner et al., 2000. UV-Induced stabilization of c-fos and other short-lived mRNAs. Mol Cell Biol, 20, 3616-25), cyclin B1 (Maity et al., 2011. Class III β-tubulin (TUBB3): More than just a biomarker for solid tumors? beta-tubulin (TUBB3): more than a biomarker in solid tumors? Curr Mol Med, 11, 726-31), HIF1α (Gudarzi et al., 2015, Endogenous tRNA-Derived Fragments Suppress Breast Cancer Progression via YBX1 Displacement. Cell, 161, 790-802), Snail (Idokiva et al., 2009, Translational activation of snail1 and other developmentally regulated transcription factors by YB-1 promotes an epithelial-mesenchymal transition. Cancer Cell, 161, 790-802). Cell 15, 402-15) and MDR1 (Bargou et al., 1997), short-lived mRNAs associated with disease progression and treatment resistance.Knockdown studies have shown that inhibition of YB-1 significantly blocks proliferation and induces apoptosis in a number of cancer models, suggesting its important role in disease progression (Idokiva et al., 2009, El-Naggar et al., 2015. Translational Activation of HIF1alpha by YB-1 Promotes Sarcoma Metastasis. Cancer Cell, 27, 682-97).YB-1 has been implicated in the development of therapeutic resistance (TR) through its roles in activating proliferation, promoting cancer cell stemness, responding to growth factors, cytokines, cellular stress responses, and promoting drug efflux via the membrane P-glycoprotein ATP-dependent efflux pump ABCB1 (MDR1) (Barhu et al., 1997. Nuclear localization and increased levels of transcription factor YB-1 in primary human breast cancers are associated with intrinsic MDR1 gene expression. Nat Med, 3, 447-50; Saupe et al., 2015. Differential expression of the multidrug resistance 1 (MDR1) protein in prostate cancer cells is independent from anticancer drug treatment and Y box binding protein 1 (YB-1) activity. 1(YB-1) activity). World J Urol, 33, 1481-6; and Mo et al., 2016, Human Helicase RECQL4 Drives Cisplatin Resistance in Gastric Cancer by Activating an AKT-YB1-MDR1 Signaling Pathway. Cancer Res, 76, 3057-66).It is also associated with alternative splicing of CD44 exons by binding to A / C-rich regions (Stickeler et al., 2001. The RNA-binding protein YB-1 binds A / C-rich exon enhancers and stimulates splicing of the CD44 alternative exon v4. EMBO J, 20, 3821-30). The YB-1 gene is highly conserved and only about 1% of cancer patients show mutations, but despite this, it is overexpressed in a variety of cancers through selective gene regulatory networks.

[0005] Ovarian cancer (OC) accounts for only 3% of all cancer cases in women but causes a disproportionate mortality (Dietl, 2014, Revisiting the pathogenesis of ovarian cancer: the central role of the fallopian tube. Arch Gynecol Obstet, 289, 241-6; Jayson et al., 2014, Ovarian cancer. Lancet, 384, 1376-88; Agarwal and Kaye, 2003, Ovarian cancer: strategies for overcoming resistance to chemotherapy. Nat Rev Cancer, 3, 502-16). Surgical resection followed by chemotherapy is the mainstay of treatment for OC. Platinum- and paclitaxel-based drugs and combinations thereof are first-line treatments for most patients with OC (Seifter, 1997, Cancer: Principles and Practice of Oncology, 5th ed.; Vincent T. DeVita, Jr., Samuel Hellman, Steven A. Rosenberg, eds. Philadelphia: Lippincott-Raven Publishers, 1997, p. 3125, illustrations ISBN 0-397-51573-4. JNCI: Journal of the National Cancer Institute 89, 353-353). Most women are diagnosed with stage III+ OC and frequently experience TR and disease recurrence.BRCA1 / 2 mutations, MYC amplification, and upregulated MDR1 (ABCB1 / P-gp) are the most common known causes of TR in OC (Zeng et al., 2018, Targeting MYC dependency in ovarian cancer through inhibition of CDK7 and CDK12 / 13. Elife, 7; Christie and Bowtell, 2017, Acquired chemotherapy resistance in ovarian cancer. Ann Oncol, 28, viii13-viii15; Sun et al., 2015, Integrative transcriptomics-based identification of cryptic drivers of taxol-resistance genes in ovarian carcinoma cells: Analysis of androgen receptor mediated paclitaxel resistance). Patient-based studies have shown that MYC amplification is associated with disease progression and TR in many high-grade epithelial OC lesions (Jung et al., 2017, A Myc Activity Signature Predicts Poor Clinical Outcomes in Myc-Associated Cancers. Cancer Research, 77, 971-981; and Jung et al., 2018, Clinical Importance of Myc Family Oncogene Aberrations in Epithelial Ovarian Cancer. JNCI Cancer Spectrum, 2).Nuclear localization of YB-1 plays an important role in the regulation of MYC, MDR1 and CD44 (Kang et al., 2013, Role of focal adhesion kinase in regulating YB-1-mediated paclitaxel resistance in ovarian cancer. J Natl Cancer Inst, 105, 1485-95; Sobocan et al., 2020, The Communication Between the PI3K / AKT / mTORPathway and Y-box Binding Protein-1in Gynecological Cancer. Cancers (Basel), 12). Analysis of high-grade ovarian serous carcinoma samples showed that patients with higher YB-1 expression had shorter survival (median survival of 48.5 months) than those with lower YB-1 expression (median survival of 65 months) (Kang et al., 2013). Primary surgical and chemotherapy treatment for OC can be followed by maintenance therapy, which includes extended use of drugs such as paclitaxel and PARP inhibitors (olaparib, pazopanib, and niraparib), but unfortunately, results remain limited (Franzese et al., 2019, PARP inhibitors in ovarian cancer, Cancer Treat Rev, 73, 1-9). The literature over the past three decades strongly suggests that YB-1 may be a potential target for the treatment of ovarian cancer and other cancers, including cancers that have developed treatment resistance. Even after extensive research, no significant efforts have been made to develop small molecule inhibitors that can directly inhibit YB-1. Y-box binding protein 1 (YB-1), encoded by the YBX1 gene, has been noted to be a regulatory or modulatory cell signaling pathway and could be considered a molecular marker of cancer progression and a target for cancer therapy.

[0006] Lasham et al., in their review article, YB-1: oncoprotein, prognostic marker and therapeutic target?, Biochem. J. (2013) 449, 11-13, describe how “YB-1 regulates multiple proliferative pathways, transcends cell cycle checkpoints, promotes replicative immortality and genomic instability, can regulate angiogenesis, plays a role in invasion and metastasis, and promotes inflammation.” They further describe cell lines in which YB-1 reduction induces apoptosis or inhibits cell proliferation, including melanoma cell lines, fibrosarcoma cell lines, hepatoma cell lines, lung cancer cell lines, bladder cancer cell lines, multiple myeloma cell lines, pediatric glioblastoma cell lines, breast cancer (ER-negative) cell lines, breast cancer (ER-positive) cell lines, prostate cancer cell lines, and colon cancer cell lines.

[0007] Sobokan et al. (Cancer, 2020, 12, 205) describe dual targeting of Y-box protein 1 (YB-1) and mTOR to improve inhibition of oncogenic activity in gynecological cancers, including ovarian, endometrial, fallopian tube, and cervical cancers.

[0008] The article Oncogenic Y-box binding protein-1 as an effective therapeutic target in drug-resistant cancer, Kuwano et al., Cancer Science, 2019, 110: 1536-1543, describes the function of YBX2 in promoting transcriptional activation of the ABCB1 transporter gene, which is related to the transcriptional mechanism of how tumors acquire multidrug resistance during chemotherapy treatment in human malignancies, including breast, lung, ovarian, prostate, colorectal, and gastric cancers.

[0009] The relationship between increased expression of YBX1 and melanoma is discussed in the article "The increased expression of Y box-binding protein 1 in melanoma stimulates proliferation and tumor invasion, antagonizes apoptosis and enhances chemoresistance" by Schittek et al., Int. J. Cancer: 120, 2110-2118 (2007). YB1 overexpression is also associated with radiation resistance in colorectal cancer cells, as discussed by Kim et al., Mol. Cancer Ther., Oct. 30, 2019, 19(2), 479-89.

[0010] WO 2019 / 178091 A1 (Malholtra et al., The Board of Trustees of the Leland Stanford Junior University) teaches novel N-hydroxyethyl didehydroazapodophyllotoxins as GBP1 inhibitors and methods for overcoming treatment resistance in cancer. Included in this disclosure is the compound 9-(3-fluorophenyl)-5-(2-hydroxyethyl)-6,9-dihydro-[1,3]dioxacyclo[4,5-g]furo[3,4-b]quinolin-8(5H)-one (SU056).

[0011] There remains a need for small molecule inhibitors of YB-1 for pharmaceutical use, particularly for the treatment of platinum-resistant cancers. Summary of the Invention

[0012] Provided is a composition comprising (S)-9-(3-fluorophenyl)-5-(2-hydroxyethyl)-6,9-dihydro-[1,3]dioxetyl[4,5-g]furo[3,4-b]quinolin-8(5H)-one or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof, wherein the composition is substantially free of (R)-9-(3-fluorophenyl)-5-(2-hydroxyethyl)-6,9-dihydro-[1,3]dioxetyl[4,5-g]furo[3,4-b]quinolin-8(5H)-one or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

[0013] BRIEF DESCRIPTION OF THE DRAWINGS

[0014] Figure 1A Presented are line graphs showing the results of an MTT cell viability assay performed in the triple-negative breast cancer cell line MDA-MB-231.

[0015] Figure 1B Presented are line graphs showing the results of an MTT cell viability assay performed in the triple-negative breast cancer cell line MDA-MB-468.

[0016] Figure 1C Presented are line graphs showing the results of an MTT cell viability assay performed in the triple-negative breast cancer cell line SUM159.

[0017] Figure 1D Presented are line graphs showing the results of an MTT cell viability assay performed in the triple-negative breast cancer cell line 4T1.

[0018] Figure 2A Presented are line graphs of the results of tumor xenograft studies of SU056 and its enantiomers in 4T1 tumor xenografts in BALB / c mice, plotted as changes in tumor volume over time.

[0019] Figure 2B Presented are line graphs of the results of tumor xenograft studies of SU056 and its enantiomers in 4T1 tumor xenografts in BALB / c mice, plotted as changes in body weight over time. DETAILED DESCRIPTION

[0020] Provided is a composition comprising (R)-9-(3-fluorophenyl)-5-(2-hydroxyethyl)-6,9-dihydro-[1,3]dioxetyl[4,5-g]furo[3,4-b]quinolin-8(5H)-one ((R)-SU506) or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable (S)-9-(3-fluorophenyl)-5-(2-hydroxyethyl)-6,9-dihydro-[1,3]dioxetine[4,5-g]furo[3,4-b]quinolin-8(5H)-one ((S)-SU506) or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

[0021] The composition herein may also refer to a composition comprising: (D)-9-(3-fluorophenyl)-5-(2-hydroxyethyl)-6,9-dihydro-[1,3]dioxetyl[4,5-g]furo[3,4-b]quinolin-8(5H)-one ((D)-SU506) or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable salt thereof. (L)-9-(3-fluorophenyl)-5-(2-hydroxyethyl)-6,9-dihydro-[1,3]dioxetine[4,5-g]furo[3,4-b]quinolin-8(5H)-one ((L)-SU506) or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof in an enantiomeric excess of (L)-9-(3-fluorophenyl)-5-(2-hydroxyethyl)-6,9-dihydro-[1,3]dioxetine[4,5-g]furo[3,4-b]quinolin-8(5H)-one ((L)-SU506) or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof.

[0022] For the sake of brevity, reference to a pharmaceutically acceptable salt of (S)-SU506 or a pharmaceutically acceptable salt of (R)-SU506 should be understood to also include reference to co-crystals, esters, solvates, hydrates, isomers (including optical isomers, racemates or other mixtures thereof), tautomers, isotopes, polymorphs or pharmaceutically acceptable prodrugs of the enantiomer in question.

[0023] Provided is a pharmaceutical composition comprising:

[0024] a) a pharmaceutically effective amount of (S)-9-(3-fluorophenyl)-5-(2-hydroxyethyl)-6,9-dihydro-[1,3]dioxetyl[4,5-g]furo[3,4-b]quinolin-8(5H)-one ((S)-SU506) or a pharmaceutically acceptable salt thereof in enantiomeric excess relative to (R)-9-(3-fluorophenyl)-5-(2-hydroxyethyl)-6,9-dihydro-[1,3]dioxetyl[4,5-g]furo[3,4-b]quinolin-8(5H)-one ((R)-SU506) or a pharmaceutically acceptable salt thereof; and

[0025] b) a pharmaceutically acceptable carrier or excipient.

[0026] The compositions herein can be used in medical treatment methods. It should be understood that for each treatment or inhibition method described herein, there are embodiments in which the term "composition" is used to refer to a composition comprising an enantiomeric excess of (S)-SU506 or a pharmaceutically acceptable salt thereof (or other forms listed above) relative to (R)-SU506 or a pharmaceutically acceptable salt thereof (or other forms listed above). For each method, there are embodiments in which the term "composition" is used to refer to a pharmaceutical composition comprising an enantiomeric excess of (S)-SU506 or other forms of (S)-SU506 listed above relative to (R)-SU506 or other forms of (R)-SU506 listed above, and a pharmaceutically acceptable excipient or carrier.

[0027] Also provided is a method for inhibiting YB1 protein activity in a subject having cancer expressing YB1 protein, the method comprising administering to a subject in need thereof a pharmaceutically effective amount of a composition comprising an enantiomeric excess of (S)-9-(3-fluorophenyl)-5-(2-hydroxyethyl)-6,9-dihydro-[1,3]dioxetyl[4,5-g]furo[3,4-b]quinolin-8(5H)-one ((R)-SU506) or a pharmaceutically acceptable salt thereof relative to (R)-9-(3-fluorophenyl)-5-(2-hydroxyethyl)-6,9-dihydro-[1,3]dioxetyl[4,5-g]furo[3,4-b]quinolin-8(5H)-one ((S)-SU506) or a pharmaceutically acceptable salt thereof.

[0028] Further provided is a method of sensitizing a subject's YB1 protein-expressing cancer cells to treatment with an anticancer agent, the method comprising administering to a subject in need thereof a pharmaceutically effective amount of a composition comprising an enantiomeric excess of (S)-9-(3-fluorophenyl)-5-(2-hydroxyethyl)-6,9-dihydro-[1,3]dioxetyl[4,5-g]furo[3,4-b]quinolin-8(5H)-one ((R)-SU506) or a pharmaceutically acceptable salt thereof relative to (R)-9-(3-fluorophenyl)-5-(2-hydroxyethyl)-6,9-dihydro-[1,3]dioxetyl[4,5-g]furo[3,4-b]quinolin-8(5H)-one ((S)-SU506) or a pharmaceutically acceptable salt thereof.

[0029] Additionally provided is a method for sensitizing a subject's YB1 protein-expressing cancer cells to treatment with radiation, the method comprising administering to a subject in need thereof a pharmaceutically effective amount of a composition comprising an enantiomeric excess of (S)-9-(3-fluorophenyl)-5-(2-hydroxyethyl)-6,9-dihydro-[1,3]dioxetyl[4,5-g]furo[3,4-b]quinolin-8(5H)-one ((S)-SU506) or a pharmaceutically acceptable salt thereof relative to (R)-9-(3-fluorophenyl)-5-(2-hydroxyethyl)-6,9-dihydro-[1,3]dioxetyl[4,5-g]furo[3,4-b]quinolin-8(5H)-one ((R)-SU506) or a pharmaceutically acceptable salt thereof.

[0030] The methods herein for treating and sensitizing a subject for a cancer expressing YB1 protein include methods for a cancer selected from the group consisting of gynecological cancer (including ovarian cancer, endometrial cancer, fallopian tube cancer, and cervical cancer), breast cancer, lung cancer, prostate cancer, colorectal cancer, bladder cancer, melanoma, liver cancer, multiple myeloma, soft tissue sarcoma, osteosarcoma, Ewing's sarcoma, glioblastoma, acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, lymphoma, kidney cancer, renal cell carcinoma, osteosarcoma, pancreatic cancer, head and neck cancer, nasopharyngeal cancer, and gastric cancer.

[0031] It should be understood that a pharmaceutically effective amount of a composition described herein can be administered concurrently with another anticancer agent or radiation in a certain regimen. In other embodiments, a pharmaceutically effective amount of a composition described herein can be administered to a subject in need thereof in a certain dose or regimen prior to the subsequent administration of a designated one or more cancer agents and / or radiation therapy.

[0032] In some embodiments, the compositions described herein can be administered over an initial period of time (eg, 1 to 7 days) followed by sequential administration of the designated one or more cancer agents and / or radiation therapy to a subject in need thereof.

[0033] In further embodiments, the compositions described herein and one or more designated cancer agents and / or radiation therapy can be administered to a subject in need thereof over repeated consecutive time periods (e.g., 1 to 14 days each) with or without a rest period between each administration pair that does not involve either treatment.

[0034] In other embodiments, the compositions described herein can be administered for an initial period of time (e.g., 1 to 7 days), followed by a second period of time in which a composition described herein and a pharmaceutically effective amount of one or more designated cancer agents and / or radiation therapy are co-administered to a subject in need thereof.

[0035] In various embodiments, the subject's YB1 (YBX1) protein-expressing cancer cells that are sensitive to or are susceptible to treatment as described herein are selected from the group consisting of gynecological cancers (including ovarian cancer, endometrial cancer, fallopian tube cancer, and cervical cancer), leukemia, lymphoma, renal cancer, bladder cancer, pancreatic cancer, head and neck cancer, breast cancer (including triple-negative breast cancer, ER-negative breast cancer, ER-positive breast cancer, and progesterone-positive breast cancer), lung cancer, ovarian cancer, prostate cancer, colorectal cancer, gastric cancer, and neuronal cancers (including gliomas).

[0036] Gynecological cancers

[0037] Provided is a method of treating a gynecological cancer expressing YB1 (YBX1) protein in a subject, the method comprising administering to the subject in need thereof a pharmaceutically effective amount of a composition described herein.

[0038] Also provided is a method for treating a gynecological cancer expressing YB1 (YBX1) protein in a subject, the method comprising administering to a subject in need thereof a pharmaceutically effective amount of a composition described herein and a pharmaceutically effective amount of an mTOR inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the mTOR inhibitor is selected from the group consisting of sirolimus, everolimus, deforolimus, and temsirolimus.

[0039] Also provided is a method for enhancing the effect of an anticancer agent in a subject having a gynecological cancer that expresses the YB1 (YBX1) protein, the method comprising administering to the subject in need thereof a pharmaceutically effective amount of a composition described herein. In some embodiments, treatment with the composition described herein sensitizes the subject's gynecological cancer cells that express the YB1 (YBX1) protein to treatment with the anticancer agent.

[0040] In some embodiments, the anticancer agent used to treat gynecological cancer is an inhibitor or antagonist of phosphoinositide 3-kinase (PI3K) / protein kinase B (Akt).

[0041] In some embodiments, the gynecological cancer expressing YB1 (YBX1) protein to be treated is ovarian cancer. In other embodiments, the gynecological cancer to be treated is endometrial cancer. In still other embodiments, the gynecological cancer to be treated is cervical cancer.

[0042] Therefore, a method of treating ovarian cancer in a subject expressing YB1 (YBX1) protein is also provided, the method comprising administering to a subject in need thereof:

[0043] a) a pharmaceutically effective amount of a composition described herein; and

[0044] b) a pharmaceutically effective amount of cisplatin or a pharmaceutically acceptable salt thereof.

[0045] In some embodiments, the taxane compound used in the methods of treating a gynecological cancer expressing the YB1 (YBX1) protein discussed herein is selected from the group consisting of paclitaxel, docetaxel, and cabazitaxel.

[0046] For each of the methods of sensitizing a subject's cancer cells expressing YB1 (YBX1) protein to treatment with an anti-cancer agent and / or radiation, or inhibiting YB1 protein activity in a subject having cancer, there is a method wherein the initial step is to detect the presence or absence of expressed YB1 (YBX1) protein in cells of a cancer sample, and upon determining the presence of YB1 (YBX1) protein in the cells of the sample, treating the subject having the cancer in question as described for each method with a pharmaceutically effective amount of a composition described herein and any other one or more agents indicated by the particular method.

[0047] As a non-limiting example, a method of treating ovarian cancer in a subject expressing YB1 (YBX1) protein is also provided, the method comprising the steps of:

[0048] a) determining the presence or absence of expressed YB1 protein in an ovarian cancer tumor sample collected from a subject in need thereof; and

[0049] b) upon determining the presence of the expressed YB1 protein in the ovarian cancer tumor sample, administering to a subject in need thereof:

[0050] i) a pharmaceutically effective amount of a composition described herein; and

[0051] ii) a pharmaceutically effective amount of a taxane compound or a pharmaceutically acceptable salt thereof.

[0052] Therefore, a method for treating fallopian tube cancer (fallopian tube carcinoma) in a subject expressing YB1 (YBX1) protein is also provided, the method comprising administering to a subject in need thereof:

[0053] a) a pharmaceutically effective amount of a composition described herein; and

[0054] b) a pharmaceutically effective amount of a taxane compound or a pharmaceutically acceptable salt thereof.

[0055] Therefore, a method for treating fallopian tube cancer (fallopian tube carcinoma) in a subject expressing YB1 (YBX1) protein is also provided, the method comprising administering to a subject in need thereof:

[0056] a) a pharmaceutically effective amount of a composition described herein;

[0057] b) a pharmaceutically effective amount of a taxane compound or a pharmaceutically acceptable salt thereof; and

[0058] c) a pharmaceutically effective amount of carboplatin or a pharmaceutically acceptable salt thereof.

[0059] In some embodiments, the taxane compound in the method of treating fallopian tube cancer is selected from the group consisting of paclitaxel, nab-paclitaxel, docetaxel, and cabazitaxel.

[0060] Prostate cancer

[0061] Also provided is a method of treating prostate cancer expressing YB1 (YBX1) protein in a subject, the method comprising administering to the subject in need thereof a pharmaceutically effective amount of the composition described herein.

[0062] Further provided is a method of inhibiting metastasis of prostate cancer expressing YB1 (YBX1) protein in a subject, the method comprising administering to a subject in need thereof a pharmaceutically effective amount of a composition described herein.

[0063] Additionally provided is a method of sensitizing a subject's prostate cancer expressing YB1 (YBX1) protein to treatment with an anti-cancer agent, the method comprising administering to a subject in need thereof a pharmaceutically effective amount of a composition described herein.

[0064] In some embodiments, administration of a composition described herein sensitizes a subject's prostate cancer expressing YB1 (YBX1) protein to treatment with a taxane anticancer agent. In some embodiments, the taxane anticancer agent is selected from the group consisting of paclitaxel, docetaxel, and cabazitaxel, or a pharmaceutically acceptable salt thereof.

[0065] Thus, also provided is a method of treating prostate cancer in a subject expressing YB1 (YBX1) protein, the method comprising administering to a subject in need thereof:

[0066] a) a pharmaceutically effective amount of a composition described herein; and

[0067] b) a pharmaceutically effective amount of a taxane compound selected from the group consisting of paclitaxel, docetaxel and cabazitaxel or a pharmaceutically acceptable salt thereof.

[0068] In some embodiments, administration of a composition described herein sensitizes a subject's prostate cancer expressing YB1 (YBX1) protein to treatment with an androgen receptor inhibitor anticancer agent. In some embodiments, the androgen receptor inhibitor is selected from the group consisting of apalutamide, enzalutamide, darolutamide, and abiraterone acetate.

[0069] Thus, also provided is a method of treating prostate cancer in a subject expressing YB1 (YBX1) protein, the method comprising administering to a subject in need thereof:

[0070] a) a pharmaceutically effective amount of a composition described herein; and

[0071] b) a pharmaceutically effective amount of an androgen receptor inhibitor compound selected from the group consisting of apalutamide, enzalutamide, darolutamide, and abiraterone acetate or a pharmaceutically acceptable salt thereof.

[0072] In some embodiments, apalutamide is administered to a subject in need thereof at a daily dose of about 100 mg to about 300 mg. In some embodiments, apalutamide is administered to a subject in need thereof at a daily dose of about 200 mg to about 300 mg. In some embodiments, apalutamide is administered to a subject in need thereof at a daily dose of about 240 mg per day.

[0073] In some embodiments, the anticancer agent is a luteinizing hormone-releasing hormone (LHRH) agonist. In some embodiments, the LHRH agonist is selected from the group consisting of leuprolide / leuprorelin, goserelin, triptorelin, buserelin, and histrelin.

[0074] Thus, also provided is a method of treating prostate cancer in a subject expressing YB1 (YBX1) protein, the method comprising administering to a subject in need thereof:

[0075] a) a pharmaceutically effective amount of a composition described herein; and

[0076] b) a pharmaceutically effective amount of a luteinizing hormone-releasing hormone (LHRH) agonist compound selected from the group consisting of leuprolide (leuprorelin), goserelin, triptorelin, buserelin and histrelin, or a pharmaceutically acceptable salt thereof.

[0077] In other embodiments, the anticancer agent is a luteinizing hormone releasing hormone (LHRH) antagonist. In some embodiments, the LHRH agonist is degarelix.

[0078] Thus, also provided is a method of treating prostate cancer in a subject, the method comprising administering to a subject in need thereof:

[0079] a) a pharmaceutically effective amount of a composition described herein; and

[0080] b) a pharmaceutically effective amount of degarelix or a pharmaceutically acceptable salt thereof.

[0081] In other embodiments, the anticancer agent is an antiandrogen. In some embodiments, the antiandrogen is selected from the group consisting of flutamide, bicalutamide, and nilutamide.

[0082] Thus, also provided is a method of treating prostate cancer in a subject expressing YB1 (YBX1) protein, the method comprising administering to a subject in need thereof:

[0083] a) a pharmaceutically effective amount of a composition described herein; and

[0084] b) a pharmaceutically effective amount of an anti-androgen compound selected from the group consisting of flutamide, bicalutamide and nilutamide or a pharmaceutically acceptable salt thereof.

[0085] In some embodiments relating to the methods herein for treating prostate cancer and / or inhibiting prostate cancer metastasis, the prostate cancer in question is non-androgen-dependent prostate cancer. In other embodiments, the prostate cancer in question is castration-sensitive prostate cancer. In other embodiments, the prostate cancer in question is metastatic castration-sensitive prostate cancer. In further embodiments, the prostate cancer expressing YB1 (YBX1) protein to be treated is non-metastatic castration-resistant prostate cancer. In other embodiments, the prostate cancer is hormone-refractory prostate cancer (HRPC).

[0086] Melanoma

[0087] Also provided is a method of treating melanoma expressing YB1 (YBX1) protein in a subject, the method comprising administering to the subject in need thereof a pharmaceutically effective amount of a composition described herein.

[0088] Further provided is a method of inhibiting metastasis of a melanoma expressing YB1 (YBX1) protein in a subject, the method comprising administering to a subject in need thereof a pharmaceutically effective amount of a composition described herein.

[0089] Additionally provided is a method of sensitizing a subject's melanoma cells expressing YB1 (YBX1) protein to treatment with an anti-cancer agent, the method comprising administering to a subject in need thereof a pharmaceutically effective amount of a composition described herein.

[0090] Thus, also provided is a method of treating melanoma expressing YB1 (YBX1) protein in a subject, the method comprising administering to a subject in need thereof:

[0091] a) a pharmaceutically effective amount of a composition described herein; and

[0092] b) a pharmaceutically effective amount of a PD-1 inhibitor selected from the group consisting of pembrolizumab and nivolumab, or a pharmaceutically acceptable salt thereof.

[0093] Further provided is a method of treating melanoma expressing YB1 (YBX1) protein in a subject, the method comprising administering to a subject in need thereof:

[0094] a) a pharmaceutically effective amount of a composition described herein; and

[0095] b) a pharmaceutically effective amount of atezolizumab or a pharmaceutically acceptable salt thereof.

[0096] Further provided is a method of treating melanoma expressing YB1 (YBX1) protein in a subject, the method comprising administering to a subject in need thereof:

[0097] a) a pharmaceutically effective amount of a composition described herein;

[0098] b) a pharmaceutically effective amount of atezolizumab or a pharmaceutically acceptable salt thereof; and

[0099] c) a pharmaceutically effective amount of a third agent selected from the group consisting of cobimetinib and vemurafenib, or a pharmaceutically acceptable salt thereof.

[0100] Also provided is a method of treating melanoma expressing YB1 (YBX1) protein in a subject, the method comprising administering to a subject in need thereof:

[0101] a) a pharmaceutically effective amount of a composition described herein; and

[0102] b) a pharmaceutically effective amount of a CTLA-4 inhibitor (such as ipilimumab).

[0103] Thus, also provided is a method of treating melanoma expressing YB1 (YBX1) protein in a subject, the method comprising administering to a subject in need thereof:

[0104] a) a pharmaceutically effective amount of a composition described herein; and

[0105] b) a pharmaceutically effective amount of interleukin-2 (IL-2).

[0106] Cisplatin resistance

[0107] YB-1 expression or overexpression has also been associated with resistance to cisplatin treatment in several cancers, including breast, bladder, and ovarian cancers.

[0108] In some embodiments, the breast cancer to be treated is refractory to endocrine therapy agents, such as selective estrogen receptor modulators (SERMs), including tamoxifen and toremifene. In some embodiments, the breast cancer is refractory to selective estrogen receptor degraders (SERDs), such as fulvestrant and elacestrant. In other embodiments, the breast cancer to be treated is refractory to aromatase inhibitors, such as letrozole, anastrozole, exemestane, and testolactone.

[0109] Provided herein is a method of sensitizing a subject's cancer expressing YB1 (YBX1) protein to treatment with cisplatin, the method comprising administering to a subject in need thereof a pharmaceutically effective amount of a composition described herein.

[0110] Provided herein is a method of sensitizing a subject's cancer expressing YB1 (YBX1) protein to treatment with a taxane compound, the method comprising administering to a subject in need thereof a pharmaceutically effective amount of a composition described herein.

[0111] Breast cancer

[0112] Also provided is a method of treating breast cancer expressing YB1 (YBX1) protein in a subject, the method comprising administering to the subject in need thereof a pharmaceutically effective amount of the composition described herein.

[0113] Further provided is a method of inhibiting metastasis of breast cancer expressing YB1 (YBX1) protein in a subject, the method comprising administering to a subject in need thereof a pharmaceutically effective amount of the composition described herein.

[0114] Additionally provided is a method of sensitizing a subject's breast cancer cells expressing YB1 (YBX1) protein to treatment with an anticancer agent, the method comprising administering to a subject in need thereof a pharmaceutically effective amount of a composition described herein. In some embodiments, the method sensitizes a subject's breast cancer cells expressing YB1 (YBX1) protein to treatment with one or more agents selected from the group consisting of anthracyclines (e.g., doxorubicin, pegylated liposomal doxorubicin, and epirubicin), taxanes (e.g., paclitaxel, nab-paclitaxel, docetaxel, and cabazitaxel), 5-fluorouracil, capecitabine, cyclophosphamide, vinarelbine, gemcitabine, ixabepilone, eribulin, and platinum agents (e.g., carboplatin and cisplatin). In other embodiments, the methods sensitize breast cancer cells expressing YB1 (YBX1) to treatment with radiation therapy.

[0115] One embodiment provides a method for treating breast cancer in a subject expressing YB1 (YBX1) protein, the method comprising administering to a subject in need thereof:

[0116] a) a pharmaceutically effective amount of a composition described herein; and

[0117] b) a pharmaceutically effective amount of one or more anticancer agents selected from the group consisting of doxorubicin, pegylated liposomal doxorubicin, epirubicin, paclitaxel, docetaxel, 5-fluorouracil, capecitabine, cyclophosphamide, and carboplatin, or a pharmaceutically acceptable salt thereof.

[0118] Another embodiment provides a method of treating breast cancer in a subject that expresses YB1 (YBX1) protein, the method comprising administering to a subject in need thereof:

[0119] a) a pharmaceutically effective amount of a composition described herein; and

[0120] b) a pharmaceutically effective amount of one or more anticancer agents selected from the group consisting of paclitaxel, nab-paclitaxel, docetaxel, doxorubicin, pegylated liposomal doxorubicin, epirubicin, cisplatin, carboplatin, vinorelbine, capecitabine, gemcitabine, ixabepilone and eribulin, or a pharmaceutically acceptable salt thereof.

[0121] Colorectal cancer

[0122] Also provided is a method of treating colorectal cancer expressing YB1 (YBX1) protein in a subject, the method comprising administering to the subject in need thereof a pharmaceutically effective amount of the composition described herein.

[0123] Further provided is a method of inhibiting metastasis of colorectal cancer expressing YB1 (YBX1) protein in a subject, the method comprising administering to a subject in need thereof a pharmaceutically effective amount of the composition described herein.

[0124] Additionally provided is a method of sensitizing a subject's colorectal cancer cells expressing YB1 (YBX1) protein to treatment with an anti-cancer agent, the method comprising administering to a subject in need thereof a pharmaceutically effective amount of a composition described herein.

[0125] Therefore, a method of treating colorectal cancer in a subject expressing YB1 (YBX1) protein is also provided, the method comprising administering to a subject in need thereof:

[0126] a) a pharmaceutically effective amount of a composition described herein; and

[0127] b) a pharmaceutically effective amount of an anticancer agent selected from the group consisting of 5-fluorouracil, capecitabine, irinotecan, oxaliplatin, trifluridine and tipiracil or a pharmaceutically acceptable salt thereof.

[0128] For each of the methods of treatment herein using a combination of trifluridine and dipivefrin (trifluridine + dipivefrin), in various embodiments, the combination of agents can include the use of separate doses of a) about 10 mg to about 20 mg of trifluridine and about 3 mg to about 10 mg of dipivefrin; b) about 12 mg to about 18 mg of trifluridine and about 4 mg to about 8 mg of dipivefrin; c) about 14 mg to about 16 mg of trifluridine and about 5 mg to about 7 mg of dipivefrin; d) about 10 mg to about 30 mg of trifluridine and about 5 mg to about 10 mg of dipivefrin; and e) about 15 mg to about 25 mg of trifluridine and about 6 mg to about 9 mg of dipivefrin. In some embodiments, a daily dose of both agents comprises about 60 mg to about 80 mg of trifluridine and about 20 mg to about 40 mg of dipivefrin. In some embodiments, the daily dose of the two agents comprises about 65 mg to about 75 mg of trifluridine and about 25 mg to about 35 mg of dipivefrin. In some embodiments, the daily dose is administered as about 30 mg to about 40 mg of trifluridine and about 12 mg to about 16 mg of trifluridine twice daily.

[0129] bladder cancer

[0130] Also provided is a method of treating bladder cancer expressing YB1 (YBX1) protein in a subject, the method comprising administering to the subject in need thereof a pharmaceutically effective amount of a composition described herein.

[0131] Further provided is a method of inhibiting metastasis of bladder cancer expressing YB1 (YBX1) protein in a subject, the method comprising administering to the subject in need thereof a pharmaceutically effective amount of the composition described herein.

[0132] Additionally provided is a method of sensitizing a subject's bladder cancer cells expressing YB1 (YBX1) protein to treatment with an anti-cancer agent, the method comprising administering to a subject in need thereof a pharmaceutically effective amount of a composition described herein.

[0133] Provided is a method of treating bladder cancer in a subject expressing YB1 (YBX1) protein, the method comprising administering to a subject in need thereof:

[0134] d) a pharmaceutically effective amount of a composition described herein;

[0135] e) a pharmaceutically effective amount of an anticancer agent selected from the group consisting of cisplatin, cisplatin plus 5-fluorouracil, and mitomycin plus 5-fluorouracil, or a pharmaceutically acceptable salt thereof;

[0136] f) therapeutically effective doses of radiation.

[0137] Also provided is a method of treating bladder cancer in a subject expressing YB1 (YBX1) protein, the method comprising administering to a subject in need thereof:

[0138] a) a pharmaceutically effective amount of a composition described herein; and

[0139] b) a pharmaceutically effective amount of an anticancer agent selected from the group consisting of:

[0140] i) gemcitabine and cisplatin;

[0141] ii) Dose-dense methotrexate, vinblastine, doxorubicin (Adriamycin), and cisplatin (DDMVAC);

[0142] iii) cisplatin, methotrexate, and vinblastine (CMV); and

[0143] iv) Gemcitabine and paclitaxel.

[0144] Also provided is a method of treating bladder cancer in a subject expressing YB1 (YBX1) protein, the method comprising administering to a subject in need thereof:

[0145] a) a pharmaceutically effective amount of a composition described herein;

[0146] b) a pharmaceutically effective amount of an anticancer agent selected from the group consisting of docetaxel, paclitaxel, doxorubicin, methotrexate, ifosfamide and pemetrexed, or a pharmaceutically acceptable salt thereof.

[0147] Liver cancer

[0148] Also provided is a method of treating liver cancer expressing YB1 (YBX1) protein in a subject, the method comprising administering to the subject in need thereof a pharmaceutically effective amount of the composition described herein.

[0149] Further provided is a method of inhibiting metastasis of liver cancer expressing YB1 (YBX1) protein in a subject, the method comprising administering to a subject in need thereof a pharmaceutically effective amount of the composition described herein.

[0150] Additionally provided is a method of sensitizing a subject's liver cancer cells expressing YB1 (YBX1) protein to treatment with an anticancer agent, the method comprising administering to a subject in need thereof a pharmaceutically effective amount of a composition described herein.

[0151] Therefore, a method of treating liver cancer expressing YB1 (YBX1) protein in a subject is also provided, the method comprising administering to a subject in need thereof:

[0152] a) a pharmaceutically effective amount of a composition described herein; and

[0153] b) a pharmaceutically effective amount of an anticancer agent selected from the group consisting of gemcitabine, oxaliplatin, cisplatin, doxorubicin, 5-fluorouracil, capecitabine and mitoxantrone, or a pharmaceutically acceptable salt thereof.

[0154] lung cancer

[0155] Also provided is a method of treating small cell lung cancer expressing YB1 (YBX1) protein in a subject, the method comprising administering to the subject in need thereof a pharmaceutically effective amount of a composition described herein.

[0156] Further provided is a method of inhibiting metastasis of small cell lung cancer expressing YB1 (YBX1) protein in a subject, the method comprising administering to the subject in need thereof a pharmaceutically effective amount of the composition described herein.

[0157] Additionally provided is a method of sensitizing a subject's small cell lung cancer cells expressing YB1 (YBX1) protein to treatment with an anti-cancer agent, the method comprising administering to a subject in need thereof a pharmaceutically effective amount of a composition described herein.

[0158] Therefore, a method of treating small cell lung cancer in a subject expressing YB1 (YBX1) protein is also provided, the method comprising administering to a subject in need thereof:

[0159] a) a pharmaceutically effective amount of a composition described herein; and

[0160] b) a pharmaceutically effective amount of an anticancer agent selected from the group consisting of cisplatin and etoposide, carboplatin and etoposide and irinotecan, and carboplatin and irinotecan, or a pharmaceutically acceptable salt thereof.

[0161] Also provided is a method of treating non-small cell lung cancer expressing YB1 (YBX1) protein in a subject, the method comprising administering to the subject in need thereof a pharmaceutically effective amount of a composition described herein.

[0162] Further provided is a method of inhibiting metastasis of non-small cell lung cancer expressing YB1 (YBX1) protein in a subject, the method comprising administering to the subject in need thereof a pharmaceutically effective amount of the composition described herein.

[0163] Additionally provided is a method of sensitizing a subject's non-small cell lung cancer cells expressing YB1 (YBX1) protein to treatment with an anti-cancer agent, the method comprising administering to a subject in need thereof a pharmaceutically effective amount of a composition described herein.

[0164] Therefore, a method of treating non-small cell lung cancer expressing YB1 (YBX1) protein in a subject is also provided, the method comprising administering to a subject in need thereof:

[0165] a) a pharmaceutically effective amount of a composition described herein; and

[0166] b) a pharmaceutically effective amount of one or more anticancer agents selected from the group consisting of cisplatin, carboplatin, paclitaxel, nab-paclitaxel, docetaxel, gemcitabine, vinorelbine, etoposide and pemetrexed, or a pharmaceutically acceptable salt thereof.

[0167] Multiple myeloma

[0168] Also provided is a method of treating multiple myeloma expressing YB1 (YBX1) protein in a subject, the method comprising administering to the subject in need thereof a pharmaceutically effective amount of a composition described herein.

[0169] Further provided is a method of inhibiting metastasis of multiple myeloma expressing YB1 (YBX1) protein in a subject, the method comprising administering to a subject in need thereof a pharmaceutically effective amount of a composition described herein.

[0170] Additionally provided is a method of sensitizing a subject's multiple myeloma cells expressing YB1 (YBX1) protein to treatment with an anti-cancer agent, the method comprising administering to a subject in need thereof a pharmaceutically effective amount of a composition described herein.

[0171] Therefore, also provided is a method of treating multiple myeloma expressing YB1 (YBX1) protein in a subject, the method comprising administering to a subject in need thereof:

[0172] a) a pharmaceutically effective amount of a composition described herein; and

[0173] b) a pharmaceutically effective amount of an anticancer agent selected from the group consisting of melphalan, vincristine, cyclophosphamide, etoposide, doxorubicin, liposomal doxorubicin and bendamustine, or a pharmaceutically acceptable salt thereof.

[0174] Soft tissue sarcoma

[0175] Also provided herein are methods for treating soft tissue sarcomas that express the YB1 (YBX1) protein, including angiosarcoma, dermatofibrosarcoma protuberans, epithelioid sarcoma, gastrointestinal stromal tumor (GIST), Kaposi's sarcoma, leiomyosarcoma, liposarcoma, malignant peripheral nerve sheath tumor, myxofibrosarcoma, rhabdomyosarcoma, solitary fibrous tumor, synovial sarcoma, and undifferentiated pleomorphic sarcoma.

[0176] Also provided is a method of treating a soft tissue sarcoma expressing YB1 (YBX1) protein (such as a fibrosarcoma expressing YB1 (YBX1) protein) in a subject, the method comprising administering to the subject in need thereof a pharmaceutically effective amount of a composition described herein.

[0177] Further provided is a method of inhibiting a soft tissue sarcoma expressing YB1 (YBX1) protein (such as a fibrosarcoma expressing YB1 (YBX1) protein) in a subject, the method comprising administering to a subject in need thereof a pharmaceutically effective amount of a composition described herein.

[0178] Additionally provided is a method of sensitizing a subject's soft tissue sarcoma cells expressing YB1 (YBX1) protein (such as fibrosarcoma cells expressing YB1 (YBX1) protein) to treatment with an anticancer agent, the method comprising administering to a subject in need thereof a pharmaceutically effective amount of a composition described herein.

[0179] Therefore, a method of treating a soft tissue sarcoma expressing YB1 (YBX1) protein (such as a fibrosarcoma expressing YB1 (YBX1) protein) in a subject is also provided, the method comprising administering to a subject in need thereof:

[0180] a) a pharmaceutically effective amount of a composition described herein; and

[0181] b) a pharmaceutically effective amount of one or more anticancer agents selected from the group consisting of ifosfamide, doxorubicin, dacarbazine (DTIC), epirubicin, temozolomide, docetaxel, gemcitabine, vinorelbine, trabectedin and eribulin or a pharmaceutically acceptable salt thereof.

[0182] In some embodiments, when the anticancer agent ifosfamide is used, the drug mesna is also administered to protect the bladder from the toxic effects of ifosfamide. In other embodiments, the anticancer agent is a combination of mesna, doxorubicin, ifosfamide, and dacarbazine, sometimes referred to by the acronym MAID. In other embodiments, the anticancer agent is a combination of doxorubicin, ifosfamide, and mesna, sometimes referred to by the acronym AIM. In some embodiments of the methods of treating soft tissue sarcomas herein, one or more anticancer agents are administered to a subject in need thereof using isolated limb perfusion.

[0183] osteosarcoma : Also provided is a method for treating osteosarcoma expressing YB1 (YBX1) protein in a subject, the method comprising administering to a subject in need thereof a pharmaceutically effective amount of the composition described herein.

[0184] Further provided is a method of inhibiting osteosarcoma expressing YB1 (YBX1) protein in a subject, the method comprising administering to a subject in need thereof a pharmaceutically effective amount of a composition described herein.

[0185] Additionally provided is a method of sensitizing a subject's osteosarcoma cells expressing YB1 (YBX1) protein to treatment with an anti-cancer agent, the method comprising administering to a subject in need thereof a pharmaceutically effective amount of a composition described herein.

[0186] Thus, also provided is a method of treating osteosarcoma expressing YB1 (YBX1) protein in a subject, the method comprising administering to a subject in need thereof:

[0187] a) a pharmaceutically effective amount of a composition described herein; and

[0188] b) a pharmaceutically effective amount of one or more anticancer agents selected from the group consisting of methotrexate, doxorubicin, cisplatin, carboplatin, ifosfamide, cyclophosphamide, etoposide and gemcitabine, or a pharmaceutically acceptable salt thereof.

[0189] In some embodiments of the above methods of treating osteosarcoma expressing YB1 (YBX1) protein, the anticancer agent is a combination of high-dose methotrexate, doxorubicin, and cisplatin (MAP regimen). In other embodiments, a combination of doxorubicin and cisplatin is administered. In other embodiments, a combination of ifosfamide and etoposide is used. In other embodiments, a combination of ifosfamide and epirubicin with cisplatin or carboplatin is administered.

[0190] Ewing's sarcoma

[0191] Also provided is a method of treating Ewing's sarcoma expressing YB1 (YBX1) protein in a subject, the method comprising administering to the subject in need thereof a pharmaceutically effective amount of a composition described herein.

[0192] Further provided is a method of inhibiting Ewing's sarcoma expressing YB1 (YBX1) protein in a subject, the method comprising administering to a subject in need thereof a pharmaceutically effective amount of a composition described herein.

[0193] Additionally provided is a method of sensitizing Ewing's sarcoma cells expressing YB1 (YBX1) protein in a subject to treatment with an anti-cancer agent, the method comprising administering to a subject in need thereof a composition described herein.

[0194] Thus, also provided is a method of treating Ewing's sarcoma expressing YB1 (YBX1) protein in a subject, the method comprising administering to a subject in need thereof:

[0195] a) a pharmaceutically effective amount of a composition described herein; and

[0196] b) a pharmaceutically effective amount of one or more anticancer agents selected from the group consisting of cyclophosphamide, doxorubicin, etoposide, ifosfamide, and vincristine, or a pharmaceutically acceptable salt thereof.

[0197] In some embodiments of the above methods of treating Ewing sarcoma expressing the YB1 (YBX1) protein, the anticancer agent is a combination of vincristine, doxorubicin, and cyclophosphamide alternating with ifosfamide and etoposide, a regimen referred to as VDC / IE.

[0198] Gastric cancer

[0199] Also provided is a method of treating gastric (stomach) cancer expressing YB1 (YBX1) protein in a subject, the method comprising administering to the subject in need thereof a pharmaceutically effective amount of the composition described herein.

[0200] Further provided is a method of inhibiting gastric cancer in a subject that expresses YB1 (YBX1) protein, the method comprising administering to the subject in need thereof a pharmaceutically effective amount of the composition described herein.

[0201] Additionally provided is a method of sensitizing a subject's gastric cancer cells expressing YB1 (YBX1) protein to treatment with an anticancer agent, the method comprising administering to the subject in need thereof a pharmaceutically effective amount of a composition described herein.

[0202] Therefore, a method for treating gastric cancer in a subject expressing YB1 (YBX1) protein is also provided, the method comprising administering to a subject in need thereof:

[0203] a) a pharmaceutically effective amount of a composition described herein; and

[0204] b) a pharmaceutically effective amount of one or more anticancer agents selected from the group consisting of 5-fluorouracil, capecitabine, carboplatin, cisplatin, docetaxel, epirubicin, irinotecan, oxaliplatin, paclitaxel, and trifluridine + dipivefrin or a pharmaceutically acceptable salt thereof.

[0205] In some embodiments of the methods for treating the above gastric cancer expressing YB1 (YBX1) protein, the anticancer agent is a combination of epirubicin, cisplatin and 5-fluorouracil, which is sometimes referred to by the acronym ECF. In other embodiments, the combination of docetaxel or paclitaxel and 5-FU or capecitabine is sometimes combined with radiation. In another embodiment, cisplatin is administered together with 5-FU or capecitabine, sometimes in combination with radiation. In further embodiments, paclitaxel and carboplatin are sometimes administered in combination with radiation. In other embodiments, a combination of docetaxel, cisplatin and 5-fluorouracil (DCF) is administered. In others, irinotecan is administered together with cisplatin, 5-fluorouracil or capecitabine. In still others, oxaliplatin is administered together with 5-fluorouracil or capecitabine. In still others, trifluridine + dipivefrin is administered.

[0207] Glioblastoma

[0208] Also provided is a method of treating glioblastoma multiforme (GBM or glioblastoma) in a subject expressing YB1 (YBX1) protein, the method comprising administering to the subject in need thereof a pharmaceutically effective amount of a composition described herein.

[0209] Further provided is a method of inhibiting glioblastoma in a subject that expresses YB1 (YBX1) protein, the method comprising administering to the subject in need thereof a pharmaceutically effective amount of the composition described herein.

[0210] Additionally provided is a method of sensitizing a subject's glioblastoma cells expressing YB1 (YBX1) protein to treatment with an anti-cancer agent, the method comprising administering to a subject in need thereof a pharmaceutically effective amount of a composition described herein.

[0211] Therefore, also provided is a method of treating a glioblastoma in a subject that expresses a YB1 (YBX1) protein, the method comprising administering to a subject in need thereof:

[0212] a) a pharmaceutically effective amount of a composition described herein; and

[0213] b) a pharmaceutically effective amount of one or more anticancer agents selected from the group consisting of temozolomide, bevacizumab, lomustine, carmustine, fluzoparil, pembrolizumab, nivolumab, ipilimumab, anlotinib, glasdegib and bavituximab, or a pharmaceutically acceptable salt thereof.

[0214] In some embodiments, the glioblastoma in the above method is a pediatric glioblastoma that expresses the YB1 (YBX1) protein. In some embodiments, the glioblastoma is a primary glioblastoma that expresses the YB1 (YBX1) protein. In others, it is a secondary glioblastoma that expresses the YB1 (YBX1) protein.

[0215] Head and neck cancer

[0216] References herein to "head and neck cancer" refer to any cancer of the oral cavity, pharynx (pharynx, including nasopharynx, oropharynx, and hypopharynx), larynx, paranasal sinuses, nasal cavity, and salivary glands. Head and neck cancer includes hypopharyngeal cancer, laryngeal cancer, lip and oral cancer, metastatic squamous cell carcinoma of the neck, nasopharyngeal cancer, oropharyngeal cancer, paranasal sinus and nasal cavity cancer, and salivary gland cancer. It should be understood that for each of the methods of treating head and neck cancer described herein, a corresponding method for each of the head and neck cancers listed in this paragraph is also disclosed.

[0217] Also provided is a method of treating head and neck cancer expressing YB1 (YBX1) protein in a subject, the method comprising administering to the subject in need thereof a pharmaceutically effective amount of a composition described herein.

[0218] Further provided is a method of inhibiting metastasis of head and neck cancer expressing YB1 (YBX1) protein in a subject, the method comprising administering to a subject in need thereof a pharmaceutically effective amount of a composition described herein.

[0219] Additionally provided is a method of sensitizing a subject's head and neck cancer expressing YB1 (YBX1) protein to treatment with an anti-cancer agent, the method comprising administering to a subject in need thereof a pharmaceutically effective amount of a composition described herein.

[0220] In some embodiments involving the treatment of head and neck cancer expressing YB1 (YBX1), the anticancer agent used to treat the subject is radiation therapy. In some embodiments, the radiation used is external beam radiation therapy. In some embodiments, the treatment comprises administering a pharmaceutically effective amount of one or more EGFR inhibitors to a subject in need thereof. Other embodiments involve administering a pharmaceutically effective amount of larotrectinib (Vitrakvi) and / or larotrectinib, respectively, to a subject in need thereof.

[0221] Other methods of treating head and neck cancer include the use of immunotherapy, such as administering a pharmaceutically effective amount of pembrolizumab and / or nivolumab to a subject in need thereof.

[0222] Provided is a method of treating head and neck cancer in a subject expressing YB1 (YBX1) protein, the method comprising administering to a subject in need thereof:

[0223] a) a pharmaceutically effective amount of a composition described herein; and

[0224] b) a pharmaceutically effective amount of an anticancer agent selected from the group consisting of paclitaxel, docetaxel, cisplatin, carboplatin, 5-fluorouracil, methotrexate and capecitabine or a pharmaceutically acceptable salt thereof.

[0225] Therefore, also provided is a method of treating head and neck cancer in a subject expressing YB1 (YBX1) protein, the method comprising administering to a subject in need thereof:

[0226] a) a pharmaceutically effective amount of a composition described herein; and

[0227] b) a pharmaceutically effective amount of a taxane compound selected from the group consisting of paclitaxel and docetaxel or a pharmaceutically acceptable salt thereof.

[0228] Also provided is a method of treating head and neck cancer in a subject expressing YB1 (YBX1) protein, the method comprising administering to a subject in need thereof:

[0229] a) a pharmaceutically effective amount of a composition described herein; and

[0230] b) a pharmaceutically effective amount of cisplatin or a pharmaceutically acceptable salt thereof.

[0231] In some embodiments, cisplatin is delivered at about 20 mg / m2 every 3 weeks x 3 times. 2 to about 100 mg / m 2 The dosage is administered to a subject in need thereof.

[0232] Also provided is a method of treating head and neck cancer in a subject expressing YB1 (YBX1) protein, the method comprising administering to a subject in need thereof:

[0233] a) a pharmaceutically effective amount of a composition described herein; and

[0234] b) a pharmaceutically effective amount of carboplatin or a pharmaceutically acceptable salt thereof; and

[0235] c) a pharmaceutically effective amount of a drug selected from the group consisting of 5-fluorouracil (5FU) and cetuximab.

[0236] Also provided is a method of treating head and neck cancer in a subject expressing YB1 (YBX1) protein, the method comprising administering to a subject in need thereof:

[0237] a) a pharmaceutically effective amount of a composition described herein; and

[0238] b) a pharmaceutically effective amount of cisplatin or a pharmaceutically acceptable salt thereof; and

[0239] c) a pharmaceutically effective amount of a drug selected from the group consisting of: 5-fluorouracil (5FU) and cetuximab.

[0240] Also provided is a method of treating head and neck cancer in a subject expressing YB1 (YBX1) protein, the method comprising administering to a subject in need thereof:

[0241] a) a pharmaceutically effective amount of a composition described herein; and

[0242] b) a pharmaceutically effective amount of cisplatin or a pharmaceutically acceptable salt thereof; and

[0243] c) a pharmaceutically effective amount of paclitaxel or a pharmaceutically acceptable salt thereof.

[0244] Also provided is a method of treating head and neck cancer in a subject expressing YB1 (YBX1) protein, the method comprising administering to a subject in need thereof:

[0245] a) a pharmaceutically effective amount of a composition described herein; and

[0246] b) a pharmaceutically effective amount of carboplatin or a pharmaceutically acceptable salt thereof; and

[0247] c) a pharmaceutically effective amount of paclitaxel or a pharmaceutically acceptable salt thereof.

[0248] Also provided is a method of treating head and neck cancer in a subject expressing YB1 (YBX1) protein, the method comprising administering to a subject in need thereof:

[0249] a) a pharmaceutically effective amount of a composition described herein; and

[0250] b) a pharmaceutically effective amount of hydroxyurea or a pharmaceutically acceptable salt thereof; and

[0251] c) a pharmaceutically effective amount of a drug selected from the group consisting of: 5-fluorouracil (5FU) and cetuximab.

[0252] Further provided is a method of treating nasopharyngeal carcinoma in a subject expressing YB1 (YBX1) protein, the method comprising administering to a subject in need thereof:

[0253] a) a pharmaceutically effective amount of a composition described herein; and

[0254] b) a pharmaceutically effective amount of hydroxyurea or a pharmaceutically acceptable salt thereof; and

[0255] c) a pharmaceutically effective amount of a drug selected from the group consisting of carboplatin, doxorubicin, epirubicin, paclitaxel, docetaxel, gemcitabine, bleomycin, and methotrexate.

[0256] pancreatic cancer

[0257] Provided is a method of treating pancreatic cancer expressing YB1 (YBX1) protein in a subject, the method comprising administering to the subject in need thereof a pharmaceutically effective amount of a composition described herein.

[0258] Further provided is a method of inhibiting metastasis of pancreatic cancer expressing YB1 (YBX1) protein in a subject, the method comprising administering to a subject in need thereof a pharmaceutically effective amount of the composition described herein.

[0259] Additionally provided is a method of sensitizing a subject's pancreatic cancer expressing YB1 (YBX1) protein to treatment with an anti-cancer agent, the method comprising administering to a subject in need thereof a pharmaceutically effective amount of a composition described herein.

[0260] Provided is a method of treating pancreatic cancer in a subject that expresses YB1 (YBX1) protein, the method comprising administering to a subject in need thereof:

[0261] a) a pharmaceutically effective amount of a composition described herein; and

[0262] b) a pharmaceutically effective amount of one or more anticancer agents selected from the group consisting of gemcitabine, 5-fluorouracil, oxaliplatin, paclitaxel, nab-paclitaxel, docetaxel, capecitabine, cisplatin and irinotecan, or a pharmaceutically acceptable salt thereof.

[0263] Neuronal cancer

[0264] The compositions described herein may also be used to treat and / or sensitize neuronal cancers (brain and spinal cord cancers) to treatment, including medulloblastoma, glioblastoma multiforme (GBM), astrocytomas (anaplastic astrocytomas and pilocytic astrocytomas), ependymomas, and oligodendrogliomas. It will be understood that for each of the following methods for treating or sensitizing neuronal cancers to treatment as described herein, a separate method for each type of neuronal cancer listed in this paragraph is included.

[0265] Provided is a method of treating a neuronal cancer expressing YB1 (YBX1) protein in a subject, the method comprising administering to the subject in need thereof a pharmaceutically effective amount of a composition described herein.

[0266] Further provided is a method of inhibiting metastasis of a neuronal cancer expressing YB1 (YBX1) protein in a subject, the method comprising administering to a subject in need thereof a pharmaceutically effective amount of a composition described herein.

[0267] Additionally provided is a method of sensitizing a subject's neuronal cancer expressing YB1 (YBX1) protein to treatment with an anti-cancer agent, the method comprising administering to a subject in need thereof a pharmaceutically effective amount of a composition described herein.

[0268] Provided is a method of treating a neuronal cancer in a subject that expresses a YB1 (YBX1) protein, the method comprising administering to a subject in need thereof:

[0269] a) a pharmaceutically effective amount of a composition described herein; and

[0270] b) a pharmaceutically effective amount of one or more anticancer agents selected from the group consisting of carboplatin, carmustine (BCNU), cisplatin, irinotecan, cyclophosphamide, etoposide, lomustine, methotrexate, procarbazine, temozolomide and vincristine, or a pharmaceutically acceptable salt thereof.

[0271] In some embodiments, a pharmaceutically effective amount of carmustine is administered to a subject in need thereof in the form of a carmustine wafer or implant, such as those available from Arbor Pharmaceuticals, LLC. Chip (carmustine implant) product.

[0272] leukemia

[0273] The methods of the present invention also include methods for treating leukemias, including acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphoblastic (or lymphocytic) leukemia (ALL), and chronic lymphocytic leukemia (CLL), wherein the leukemia cells in question express YB-1 protein. It should be understood that for each method described herein for treating or sensitizing a leukemia to treatment, a separate corresponding method should be understood as being for each of the leukemias mentioned (AML, CML, ALL, and CLL).

[0274] Additionally provided is a method of sensitizing a subject's leukemia cells expressing YB1 (YBX1) protein to treatment with an anticancer agent, the method comprising administering to the subject in need thereof a pharmaceutically effective amount of a composition described herein. In some embodiments, the anticancer agent used to treat the subject is radiation therapy.

[0275] Also provided is a method of treating acute myeloid leukemia in a subject expressing YB1 (YBX1) protein, the method comprising administering to a subject in need thereof:

[0276] a) a pharmaceutically effective amount of a composition described herein; and

[0277] b) a pharmaceutically effective amount of an anthracycline selected from the group consisting of daunorubicin and idarubicin, or a pharmaceutically acceptable salt thereof; and

[0278] c) a pharmaceutically effective amount of cytarabine or a pharmaceutically acceptable salt thereof.

[0279] Also provided is a method of treating acute myeloid leukemia in a subject expressing YB1 (YBX1) protein, the method comprising administering to a subject in need thereof:

[0280] a) a pharmaceutically effective amount of a composition described herein; and

[0281] b) a pharmaceutically effective amount of one or more anticancer agents selected from the group consisting of cladribine (2-CdA), fludarabine, mitoxantrone, etoposide, 6-thioguanine, hydroxyurea, prednisone, dexamethasone, methotrexate, 6-mercaptopurine, azacitidine and decitabine, or a pharmaceutically acceptable salt thereof.

[0282] Also provided is a method of treating chronic myeloid leukemia in a subject expressing YB1 (YBX1) protein, the method comprising administering to a subject in need thereof:

[0283] a) a pharmaceutically effective amount of a composition described herein; and

[0284] b) a pharmaceutically effective amount of one or more anticancer agents selected from the group consisting of hydroxyurea, cytarabine (Ara-C), busulfan, cyclophosphamide and vincristine or a pharmaceutically acceptable salt thereof.

[0285] Also provided is a method of treating chronic myeloid leukemia in a subject expressing YB1 (YBX1) protein, the method comprising administering to a subject in need thereof:

[0286] a) a pharmaceutically effective amount of a composition described herein; and

[0287] b) a pharmaceutically effective amount of one or more tyrosine kinase inhibitor anticancer agents selected from the group consisting of: imatinib dasatinib Nilotinib bosutinib Ponatinib and Asciminids or a pharmaceutically acceptable salt thereof.

[0288] Also provided is a method of treating chronic myeloid leukemia in a subject expressing YB1 (YBX1) protein, the method comprising administering to a subject in need thereof:

[0289] a) a pharmaceutically effective amount of a composition described herein; and

[0290] b) a pharmaceutically effective amount of interferon-α or a pharmaceutically acceptable salt thereof.

[0291] Also provided is a method of treating acute lymphoblastic leukemia in a subject expressing YB1 (YBX1) protein, the method comprising administering to a subject in need thereof:

[0292] a) a pharmaceutically effective amount of a composition described herein; and

[0293] b) a pharmaceutically effective amount of one or more anticancer agents selected from the group consisting of vincristine, dexamethasone, imatinib, prednisone, doxorubicin and daunorubicin or a pharmaceutically acceptable salt thereof.

[0294] Also provided is a method of treating acute lymphoblastic leukemia in a subject expressing YB1 (YBX1) protein, the method comprising administering to a subject in need thereof:

[0295] a) a pharmaceutically effective amount of a composition described herein; and

[0296] b) a pharmaceutically effective amount of one or more anticancer agents selected from the group consisting of methotrexate, 6-mercaptopurine, vincristine, prednisone and imatinib, or a pharmaceutically acceptable salt thereof.

[0297] Also provided is a method of treating acute lymphoblastic leukemia in a subject expressing YB1 (YBX1) protein, the method comprising administering to a subject in need thereof:

[0298] a) a pharmaceutically effective amount of a composition described herein; and

[0299] b) a pharmaceutically effective amount of one or more anticancer agents selected from the group consisting of vincristine, dexamethasone, prednisone, doxorubicin and daunorubicin or a pharmaceutically acceptable salt thereof.

[0300] Also provided is a method of treating acute lymphoblastic leukemia in a subject expressing YB1 (YBX1) protein, the method comprising administering to a subject in need thereof:

[0301] a) a pharmaceutically effective amount of a composition described herein; and

[0302] b) a pharmaceutically effective amount of one or more anticancer agents selected from the group consisting of methotrexate, 6-mercaptopurine (6-MP), vincristine, prednisone and imatinib, or a pharmaceutically acceptable salt thereof.

[0303] Also provided is a method of treating chronic lymphocytic leukemia in a subject expressing YB1 (YBX1) protein, the method comprising administering to a subject in need thereof:

[0304] a) a pharmaceutically effective amount of a composition described herein; and

[0305] b) a pharmaceutically effective amount of one or more anticancer agents selected from the group consisting of ibrutinib, acalabrutinib, idelalisib and duvelisib, or pharmaceutically acceptable salts thereof.

[0306] Also provided is a method of treating chronic lymphocytic leukemia in a subject expressing YB1 (YBX1) protein, the method comprising administering to a subject in need thereof:

[0307] a) a pharmaceutically effective amount of a composition described herein; and

[0308] b) a pharmaceutically effective amount of venetoclax or a pharmaceutically acceptable salt thereof.

[0309] Also provided is a method of treating chronic lymphocytic leukemia in a subject expressing YB1 (YBX1) protein, the method comprising administering to a subject in need thereof:

[0310] a) a pharmaceutically effective amount of a composition described herein; and

[0311] c) a pharmaceutically effective amount of one or more anticancer agents selected from the group consisting of rituximab, ofatumumab and obinutuzumab, or a pharmaceutically acceptable salt thereof.

[0312] definition

[0313] The terms "YB1" and "YBX1" refer to Y-box binding protein 1, also known as Y-box transcription factor or nuclease-sensitive element binding protein 1, a protein that in humans is encoded by the YBX1 gene.

[0314] In some embodiments, a "subject in need thereof" involving the methods of treatment herein is a patient from whom a tumor sample is extracted (e.g., by tumor biopsy) and the presence of expressed YBX1 protein is identified in the sampled material, such as by immunohistochemistry or Western blotting techniques known in the art.

[0315] The terms "effective amount," "therapeutically effective amount," or "pharmaceutically effective amount" refer to an amount sufficient to achieve treatment as defined below when administered to a subject (e.g., a mammal, such as a human) in need of such treatment. The therapeutically or pharmaceutically effective amount will vary depending on the subject and disease condition being treated, the subject's weight and age, the severity of the disease condition, the mode of administration, and the like, all of which can be readily determined by one of ordinary skill in the art. For example, an "effective amount," "therapeutically effective amount," or "pharmaceutically effective amount" of a composition described herein is an amount sufficient to modulate YXB1 expression or activity and thereby treat a subject (e.g., a human) suffering from an indicated condition or to ameliorate or alleviate existing symptoms of an indicated condition. For example, a therapeutically or pharmaceutically effective amount can be an amount sufficient to alleviate the symptoms of a disease or condition in response to inhibition of YXB1 activity.

[0316] In some embodiments, an "effective amount" is an amount of a compound that, when administered to a subject at one or more doses in monotherapy or combination therapy, is effective to inhibit YB-1 by about 20% (20% inhibition), at least about 30% (30% inhibition), at least about 40% (40% inhibition), at least about 50% (50% inhibition), at least about 60% (60% inhibition), at least about 70% (70% inhibition), at least about 80% (80% inhibition), or at least about 90% (90% inhibition) compared to the activity of YB-1 in the subject in the absence of treatment with the subject compound, or alternatively, compared to the activity of YB-1 in the subject before or after treatment with the compound.

[0317] In some embodiments, an "effective amount" is an amount of the compound that, when administered to an individual at one or more doses in monotherapy or combination therapy, is effective to reduce the tumor burden of the subject by about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%, compared to the tumor burden of the subject in the absence of treatment with the subject compound, or alternatively, compared to the tumor burden of the subject before or after treatment with the compound. As used herein, the term "tumor burden" refers to the total mass of tumor tissue carried by a subject suffering from cancer. In some embodiments, an "effective amount" is an amount of the compound that, when administered to an individual at one or more doses in monotherapy or combination therapy, is effective to reduce the dose of radiation therapy required to observe tumor reduction in the subject by about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%, compared to the dose of radiation therapy required to observe tumor reduction in the subject in the absence of treatment with the subject compound. In some embodiments, an "effective amount" of a compound is an amount effective to achieve a 1.5-log, 2-log, 2.5-log, 3-log, 3.5-log, 4-log, 4.5-log, or 5-log reduction in tumor size when administered at one or more doses to an individual suffering from cancer.

[0318] In some embodiments, (S)-9-(3-fluorophenyl)-5-(2-hydroxyethyl)-6,9-dihydro-[1,3]dioxetine[4,5-g]furo[3,4-b]quinolin-8(5H)-one or a pharmaceutically acceptable salt thereof can be administered at a daily dose of about 0.2 mg / kg to about 10 mg / kg. In other embodiments, it can be administered at a daily dose of about 0.2 mg / kg to about 5 mg / kg.

[0319] In some embodiments, an effective amount of (S)-9-(3-fluorophenyl)-5-(2-hydroxyethyl)-6,9-dihydro-[1,3]dioxacyclo[4,5-g]furo[3,4-b]quinolin-8(5H)-one or a pharmaceutically acceptable salt thereof is from about 50 ng / kg body weight to about 50 pg / kg body weight (e.g., from about 50 ng / kg body weight to about 40 pg / kg body weight, from about 30 ng / kg body weight to about 20 pg / kg body weight, from about 50 ng / kg body weight to about 10 pg / kg body weight, from about 50 ng / kg body weight to about 1 pg / kg body weight, from about 50 ng / kg body weight to about 800 ng / kg body weight, from about 50 ng / kg body weight to about 700 ng / kg body weight, from about 50 ng / kg body weight to about 600 ng / kg body weight, from about 50 ng / kg body weight to about 500 ng / kg body weight, from about 50 ng / kg body weight to about 600 ng / kg body weight,

[0014] In some embodiments, the present invention provides an amount within the range of about 150 ng / kg body weight to about 400 ng / kg body weight, about 60 ng / kg body weight to about 400 ng / kg body weight, about 70 ng / kg body weight to about 300 ng / kg body weight, about 60 ng / kg body weight to about 100 ng / kg body weight, about 65 ng / kg body weight to about 85 ng / kg body weight, about 70 ng / kg body weight to about 90 ng / kg body weight, about 200 ng / kg body weight to about 900 ng / kg body weight, about 200 ng / kg body weight to about 800 ng / kg body weight, about 200 ng / kg body weight to about 700 ng / kg body weight, about 200 ng / kg body weight to about 600 ng / kg body weight, about 200 ng / kg body weight to about 500 ng / kg body weight, about 200 ng / kg body weight to about 400 ng / kg body weight, or about 200 ng / kg body weight to about 300 ng / kg body weight).

[0320] In some embodiments, an effective amount of (S)-9-(3-fluorophenyl)-5-(2-hydroxyethyl)-6,9-dihydro-[1,3]dioxacyclo[4,5-g]furo[3,4-b]quinolin-8(5H)-one or a pharmaceutically acceptable salt thereof is from about 10 pg to about 100 mg, for example, from about 10 pg to about 50 pg, from about 50 pg to about 150 pg, from about 150 pg to about 250 pg, from about 250 pg to about 500 pg, from about 500 pg to about 750 pg, from about 750 pg to about 1 ng, from about 1 ng to about 10 ng, from about 10 ng to about 250 pg, from about 250 pg to about 500 pg, from about 500 pg to about 750 pg, from about 750 pg to about 1 ng, from about 1 ng to about 10 ng, from about 10 ng to about 250 pg. The amount in the range of about 50ng, about 50ng to about 150ng, about 150ng to about 250ng, about 250ng to about 500ng, about 500ng to about 750ng, about 750ng to about 1pg, about 1pg to about 10pg, about 10pg to about 50pg, about 50mg to about 150gg, about 150gg to about 250gg, about 250gg to about 500gg, about 500gg to about 750gg, about 750gg to about 1g, about 1mg to about 50mg, about 1mg to about 100mg or about 50mg to about 100mg. The amount can be a single dose amount or can be a total daily amount. The total daily amount can be in the range of 10pg to 100mg, or can be in the range of 100mg to about 500mg, or can be in the range of 500mg to about 1000mg. In other embodiments, daily dose or daily amount are 1mg to 1,000mg. In other embodiments, the daily dose or daily amount is 10 mg to 1,000 mg. In further embodiments, the daily dose or daily amount is 10 mg to 750 mg. In further embodiments, the daily dose or daily amount is 10 mg to 500 mg. In further embodiments, the daily dose or daily amount is 100 mg to 500 mg.

[0321] In some embodiments, a single dose of (S) -9- (3- fluorophenyl) -5- (2- hydroxyethyl) -6,9- dihydro - [1,3] dioxetyl [4,5-g] furano [3,4-b] quinoline -8 (5H) -one or a pharmaceutically acceptable salt thereof is administered. In other embodiments, multiple doses are administered. When multiple doses are administered over a certain period of time, the compound can be administered twice daily (qid), daily (qd), every other day (qod), every three days, three times a week (tiw) or twice a week (biw) over a certain period of time. For example, the compound is administered twice daily, daily, every other day, three times a week or twice a week over a period of one day to about 2 years or longer. For example, (S)-9-(3-fluorophenyl)-5-(2-hydroxyethyl)-6,9-dihydro-[1,3]dioxetyl[4,5-g]furo[3,4-b]quinolin-8(5H)-one or a pharmaceutically acceptable salt thereof is administered at any of the aforementioned frequencies for one week, two weeks, one month, two months, six months, one year, or two years or longer, depending on various factors.

[0322] Administration of an effective amount of (S)-9-(3-fluorophenyl)-5-(2-hydroxyethyl)-6,9-dihydro-[1,3]dioxetyl[4,5-g]furo[3,4-b]quinolin-8(5H)-one or a pharmaceutically acceptable salt thereof to an individual suffering from cancer can result in one or more of the following: 1) a reduction in tumor burden; 2) a reduction in the dose of radiation therapy required to achieve tumor shrinkage (e.g., due to sensitivity to radiation therapy); 3) a reduction in the spread of cancer from one cell to another in the individual; 4) a reduction in morbidity or mortality in clinical outcomes; 5) a reduction in the overall length of treatment when combined with other anticancer agents (e.g., due to sensitivity to other anticancer agents); and 6) an improvement in indicators of disease response (e.g., a reduction in one or more symptoms of cancer). Any of a variety of methods can be used to determine whether a treatment method is effective. For example, a biological sample obtained from an individual treated with the subject method can be assayed.

[0323] The stereochemical definitions and conventions used herein generally follow those in SP Parker, ed., McGraw-Hill Dictionary of Chemical Terms (1984), McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., Stereochemistry of Organic Compounds (1994), John Wiley & Sons, Inc., New York. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. When describing an optically active compound, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule about its chiral center. The prefixes d and l, D and L, or (+) and (-) are used to indicate the sign of rotation of plane-polarized light by the compound, where S, (-) or l indicates that the compound is levorotatory, while a compound prefixed with R, (+) or d indicates that it is dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. A specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often referred to as an enantiomeric mixture. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomeric species that is devoid of optical activity.

[0324] As used herein, "substantially free" when referring to enantiomers means that the composition comprises a greater weight of (S)-(-)-SUO56 than the weight of (R)-(+)-SUO56. In some embodiments, the composition comprises at least 60% by weight of (S)-(-)-SUO56, or a pharmaceutically acceptable salt thereof, and no more than 40% by weight of (R)-(+)-SUO56, or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises at least 70% by weight of (S)-(-)-SUO56, or a pharmaceutically acceptable salt thereof, and no more than 30% by weight of (R)-(+)-SUO56, or a pharmaceutically acceptable salt thereof. In other embodiments, the composition comprises at least 80% by weight of (S)-(-)-SUO56, or a pharmaceutically acceptable salt thereof, and no more than 20% by weight of (R)-(+)-SUO56, or a pharmaceutically acceptable salt thereof. In additional embodiments, the composition comprises at least 90% (S)-(-)-SUO56 or a pharmaceutically acceptable salt thereof and no more than 10% (R)-(+)-SUO56 or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises at least 95% (S)-(-)-SUO56 or a pharmaceutically acceptable salt thereof and no more than 5% (R)-(+)-SUO56 or a pharmaceutically acceptable salt thereof. In various embodiments, the composition comprises at least 98% (S)-(-)-SUO56 or a pharmaceutically acceptable salt thereof and no more than 2% (R)-(+)-SUO56 or a pharmaceutically acceptable salt thereof. In further embodiments, the composition comprises at least 99% (S)-(-)-SUO56 or a pharmaceutically acceptable salt thereof and no more than 1% (R)-(+)-SUO56 or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises at least 99.9% (S)-(-)-SUO56 or a pharmaceutically acceptable salt thereof and no more than 0.1% (R)-(+)-SUO56 or a pharmaceutically acceptable salt thereof. All percentages given above for enantiomers are weight percentages.

[0325] The relative presence or concentration of enantiomers can also be characterized as "enantiomeric excess (ee or EE)", which refers to the extent to which one enantiomer is present in a greater amount than its counterpart. For example, the enantiomeric excess of a racemic mixture is 0%, while the enantiomeric excess of a pure enantiomer is 100%. A sample having 80% of one enantiomer and 20% of the other enantiomer has an enantiomeric excess of 60% (80% minus 20%). In separate examples, the enantiomeric excess of (S)-(-)-SUO56 relative to (R)-(+)-SUO56 can be 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, and 99.9%, respectively. In other embodiments, the composition comprises 100% (S)-(-)-SUO56 because the presence of (R)-(+)-SUO56 is too low to be detected by conventional means.

[0326] A "subject" refers to an animal, such as a mammal, that has been or will be the subject of treatment, observation, or experiment. The methods described herein can be used for both human therapy and veterinary applications. In some embodiments, the subject is a mammal; in some embodiments, the subject is a human; and in some embodiments, the subject is selected from cats and dogs. A "subject in need" or "human in need" refers to a subject, such as a human, who may have or is suspected of having a disease or condition that would benefit from certain treatments, such as treatment with a composition described herein, or a pharmaceutically acceptable salt or cocrystal thereof. This includes subjects who may be determined to be at risk for or susceptible to such diseases or conditions, such that treatment will prevent the disease or condition.

[0327] "Treatment" or "treating" is a method for obtaining a beneficial or desired result, including a clinical result. Beneficial or desired clinical results can include one or more of the following: (i) inhibiting a disease or condition (e.g., alleviating one or more symptoms caused by the disease or condition, and / or reducing the extent of the disease or condition); (ii) slowing or inhibiting the development of one or more clinical symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, preventing or delaying the worsening or progression of the disease or condition, and / or preventing or delaying the spread of the disease or condition (e.g., metastasis)); and / or (iii) relieving the disease, i.e., causing a regression of clinical symptoms (e.g., improving the disease state, providing partial or complete remission of the disease or condition, enhancing the effect of another drug, delaying the progression of the disease, improving quality of life, and / or prolonging survival).

[0328] The term "inhibiting" or "inhibition" means that the baseline activity of a biological activity or process is reduced, such as significantly reduced. "Inhibition of YB-1 activity" means that, as a direct or indirect response to the presence of a composition described herein, YB-1 activity is reduced relative to the activity of YB-1 in the absence of such compound or its pharmaceutically acceptable salt or co-crystal. The reduction in activity may be due to a direct interaction between the compound and YB-1, or due to the interaction between the compound described herein and one or more other factors that affect the activity of YB-1. For example, the presence of the compound can reduce YB-1 activity by directly binding to YB-1, by (directly or indirectly) causing another factor to reduce YB-1 activity, or by (directly or indirectly) reducing the amount of YB-1 present in a cell or organism. In some embodiments, the inhibition of YB-1 activity can be compared in the same subject before treatment or in other subjects that have not received treatment. The term "inhibitor" is understood to refer to a compound or agent that provides the desired inhibitory activity after administration to a person in need at a pharmaceutically or therapeutically effective dose.

[0329] The term "pharmaceutical composition" refers to a composition containing a pharmaceutically effective amount of one or more of the isotopic compounds described herein or their pharmaceutically acceptable salts, formulated together with a pharmaceutically acceptable carrier, which may also include other additives and is manufactured or sold as part of a therapeutic regimen for treating a disease in a mammal approved by a governmental regulatory agency. The pharmaceutical composition can be formulated, for example, for oral administration in a unit dosage form (e.g., tablets, capsules, caplets, softgels, or syrups); for topical administration (e.g., in the form of a cream, gel, lotion, or ointment); for intravenous administration (e.g., as a sterile solution free of particulate emboli and a solvent system suitable for intravenous use); or formulated in any other formulation described herein. General procedures and ingredients for selecting and preparing suitable formulations are described, for example, in Remington: The Science and Practice of Pharmacy, 21st edition, Gennaro, ed., Lippencott Williams & Wilkins (2005), and in The United States Pharmacopeia: The National Formulary (USP 36NF31), published in 2013.

[0330] As used herein, a "pharmaceutically acceptable excipient" is a pharmaceutically acceptable vehicle, including, but not limited to, any and all carriers, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Unless any conventional media or agents are incompatible with the active ingredient, their use in therapeutic compositions is contemplated. Supplementary active ingredients may also be incorporated into the compositions.

[0331] The term "pharmaceutically acceptable carrier" refers to any ingredient in a pharmaceutical composition other than a disclosed pharmaceutically active compound or therapeutic compound or a pharmaceutically acceptable salt thereof (e.g., a carrier capable of suspending or dissolving an active isotope compound) that is non-toxic and non-inflammatory to the patient. Excipients may include, for example, anti-adherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colorants), emollients, emulsifiers, fillers (diluents), film formers or coatings, flavorings, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, adsorbents, suspending or dispersing agents, sweeteners, and water of hydration. Exemplary excipients include, but are not limited to, butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, cross-linked carboxymethylcellulose, cross-linked polyvinyl pyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methylparaben, microcrystalline cellulose, polyethylene glycol, polyvinyl pyrrolidone, povidone, pregelatinized starch, propylparaben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethylcellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol.

[0332] The term "pharmaceutically acceptable salt" includes, for example, salts with inorganic acids and salts with organic acids. Examples of salts can include hydrochlorides, phosphates, diphosphates, hydrobromides, sulfates, sulfinates, nitrates, malates, maleates, fumarates, tartrates, succinates, citrates, acetates, lactates, methanesulfonates (mesylate), benzenesulfonates (benzenesuflonate / besylate), p-toluenesulfonates (toluenesulfonate), 2-hydroxyethylsulfonates, benzoates, salicylates, stearates, and alkanoates (such as acetate, HOOC-(CH2) n-COOH, wherein n is 0-4). In addition, if the compounds described herein are obtained in the form of acid addition salts, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, can be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid according to conventional procedures for preparing acid addition salts from basic compounds. Those skilled in the art will recognize various synthetic methods that can be used to prepare non-toxic pharmaceutically acceptable addition salts.

[0333] The term "crystalline form" and related terms herein refer to various crystalline modifications of a given substance, including but not limited to polymorphs, solvates, hydrates, co-crystals and other molecular complexes, as well as salts, solvates of salts, hydrates of salts, other molecular complexes of salts, and polymorphs thereof. Crystalline forms of a substance can be obtained by a variety of methods as known in the art. Such methods include but are not limited to melt recrystallization, melt cooling, solvent recrystallization, recrystallization in a confined space (e.g., in a nanopore or capillary), recrystallization on a surface or template (e.g., on a polymer), recrystallization in the presence of additives (e.g., co-crystal antimolecules), desolvation, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, sublimation, grinding, and solvent drop grinding.

[0334] As used herein with respect to cancer, the term "refractory" refers to a cancer that has not responded to one or more treatments. In some embodiments, the cancer is unresponsive to one or more chemotherapeutic agents. In other embodiments, the cancer is unresponsive to radiation therapy. In other embodiments, a refractory cancer is unresponsive to one or more chemotherapeutic agents and radiation therapy. A refractory cancer may be resistant at the start of such treatments, or may become resistant over the course of one or more treatments. In the context of chemotherapy, a refractory cancer may also be referred to as a "chemotherapy-resistant cancer" or "chemoresistant cancer." A "platinum-resistant cancer" is a cancer that initially responds to treatment with a drug containing platinum, such as cisplatin, carboplatin, oxaliplatin, nedaplatin, lobaplatin, triplatin tetranitrate, and picoplatin, but returns within a certain period of time. For example, ovarian cancer that returns within 6 months of treatment is considered platinum-resistant. For each of the treatment methods described herein, there is an additional embodiment in which the cancer in question is a platinum-resistant cancer.

[0335] "Androgen-independent prostate cancer" or "hormone-refractory prostate cancer (AIPC)" is a prostate cancer that progresses after the addition of anti-androgens and subsequent withdrawal of anti-androgens following initial androgen ablation therapy starting with orchiectomy or gonadotropin-releasing hormone (LHRH) agonists. In some embodiments, hormone-refractory prostate cancer is defined as 2-3 consecutive increases in prostate-specific antigen (PSA) levels obtained at intervals greater than 2 weeks, and / or disease progression based on records of findings from CT scans and / or bone scans, bone pain, or obstructive urination symptoms. In some embodiments, PSA levels do not rise at the time of diagnosis or during the entire course of the disease. In some embodiments, prostate cancer is advanced prostate cancer. In some embodiments, prostate cancer or metastatic prostate cancer is resistant to treatment with hormone-blocking therapy, such as abiraterone. Enzalutamide Bicalutamide Flutamide or cyproterone acetate

[0336]

[0337] Cancer cells that develop resistance to radiation therapy, either inherently or acquired over time, are referred to as “radiation resistant cancer.” These terms are intended to describe cancer cells that are less responsive to radiation therapy than non-resistant cancer cells are to radiation therapy.

[0338] All ranges disclosed and / or claimed herein are inclusive of the recited endpoints and are independently combinable. For example, a range of "2 to 10" and "2-10" includes the endpoints 2 and 10, and all intermediate values ​​between the context of the unit being considered. For example, unless described in the context of an average, a reference to "claims 2 to 10" or "C2-C 10 References to "alkyl" include units 2, 3, 4, 5, 6, 7, 8, 9, and 10, as the claims and atoms are numbered as consecutive numbers without fractions or decimal points. On the other hand, the context of "a pH of 5-9" or "a temperature of 5°C to 9°C" includes the integers 5, 6, 7, 8, and 9, and all fractional and decimal units therebetween, such as 6.5 and 8.24.

[0339] "Significant" means any detectable change that is statistically significant in a standard parametric test of statistical significance, such as Student's T-test, where p < 0.05.

[0340] The modifier "about" used in conjunction with a quantity is inclusive of the stated value and has the meaning dictated by the context (e.g., includes the degree of error associated with measurement of the particular quantity). In some embodiments, the term "about" refers to the stated amount plus or minus 10%. In some embodiments, the term "about" refers to the stated amount plus or minus 5%.

[0341] Procedure for the Synthesis of 9-(3-fluorophenyl)-5-(2-hydroxyethyl)-6,9-dihydro-[1,3]dioxacyclo[4,5-g]furo[3,4-b]quinolin-8(5H)-one

[0342]

[0343] Materials and methods

[0344] All reagents and solvents were obtained from sources such as Sigma-Aldrich, Fisher Scientific, Acros organics, Alfa-Aesar, ChemScene, and Chem-Implex with the highest commercial quality and were used without further purification. Reactions were monitored by TLC using pre-coated silica gel plates (Merck, silica gel 60 F254). Flash chromatography was performed using a CombiFlash Rf+Lu-men chromatography system (Teledyne ISCO, Lincon, NE, USA). The HPLC-MS spectra were taken as follows: 1H (400 MHz) and 13C (101 MHz) NMR spectra were recorded using a suitable deuterated solvent on an Agilent 400-MR NMR or Bruker Avance 400 MHz spectrometer. Chemical shifts (δ) were reported in parts per million (ppm) from tetramethylsilane (TMS) as an internal standard to high field. Coupling constants (J) were reported in Hertz (Hz), and s, br.s, d, t, and m represent unimodal, broad unimodal, doublet, triplet, and multiplet, respectively. LC-MS spectra were recorded on an Agilent 6490iFunnel triple quadrupole mass spectrometer from Agilent Technologies (Santa Clara, CA, USA). LC-MS analysis was performed using an Agilent Eclipse Plus C18 reverse phase column 1.8 μm, 2.1 x 50 mm with solvent A (acetonitrile containing 0.1% formic acid) and solvent B (water containing 0.1% formic acid). The ratio of solvent A to solvent B was 1:9 at the beginning and gradually changed to 9:1 at the end.

[0345] Synthesis of 2-(Benzo[d][1,3]dioxol-5-ylamino)ethan-1-ol (2):

[0346]

[0347] The title compound was prepared according to the method reported previously with some modifications to 1-3. Under a nitrogen atmosphere, at room temperature (rt), benzo [d] [1,3] dioxole-5-amine (30g, 0.218mol) was added to dry dichloromethane (500mL). Pyridine (22.49g, 0.284mol) and 2-chloroethyl chloroformate (32.8g, 0.229mol) were slowly added to this solution under stirring. The mixture was stirred at room temperature for 3 hours and washed with water (4x 100mL). The organic layer was dried over Na2SO4, filtered, and evaporated to dryness using a rotary evaporator. The crude material was dissolved in ethanol (350mL), processed with NaOH (35g, 0.875mol), and heated at 90°C overnight. The solvent was evaporated by a rotary evaporator. The solid obtained was dissolved in a large amount of ethyl acetate (EtOAc), and then washed with water, followed by washing with a saline solution. The organic phase was dried over Na 2 SO 4 , filtered, and evaporated to dryness to give the crude product, which was purified on a silica gel column using a 0-50% gradient of EtOAc / hexanes to afford the desired product (20 g, 51%) as a light brown oil.

[0348] Synthesis of 9-(3-fluorophenyl)-5-(2-hydroxyethyl)-6,9-dihydro-[1,3]dioxetine[4,5-g]furo[3,4-b]quinolin-8(5H)-one (5,SU-056):

[0349] Synthesis of novel functionalized 4-aza-2,3-didehydropodophyllotoxin derivatives with potential antitumor activity was performed according to previously reported methods (Kumar, A.; Alegria, AE). Journal of heterocyclic chemistry Chemistry, 2010, 47(6), 1275; Andreoli, M.; Persico, M.; Kumar, A.; Orteca, N.; Kumar, V.; Pepe, A.; Mahalingam, S.; Alegria, A.E.; Petrella, L.; Sevciunaite, L. Identification of the first inhibitor of the GBP1:PIM1 interaction. Implications for the development of a new class of anticancer agents against paclitaxel resistant cancer cells. Journal of medicinal chemistry Chemistry, 2014, 57(19), 7916-7932; and Resendez, A.; Tailor, D.; Graves, E.; Malhotra, SV. Radiosensitization of Head and Neck Squamous Cell Carcinoma (HNSCC) by a Podophyllotoxin.The title compound was prepared in ACS medicinal chemistry letters 2019, 10(9), 1314-1321 with several modifications. 2-(Benzo[d][1,3]dioxol-5-ylamino)ethan-1-ol 2 (16 g, 0.088 mol), tetronic acid 3 (10.5 g, 0.105 mol), 3-fluorobenzaldehyde 4 (13.5 g, 0.105 mol) and L-proline (1.01 g, 0.008 mmol) were added to dry ethanol (400 mL) under nitrogen atmosphere. The reaction mixture was refluxed overnight. After consumption of 2, the reaction mixture was evaporated to dryness. The crude product was purified on a silica gel column using a 0-50% gradient of EtOAc / hexane to obtain the desired product. The product was recrystallized from ethanol to give the desired compound (12.1 g, 37%). 1H NMR(400MHz,DMSO-d6)δ7.29(td,J=7.9,6.1Hz,1H),7.13–6.92(m,4H),6.66 (s,1H),5.96(dd,J=24.7,1.1Hz,2H),5.19–4.91(m,4H),4.04–3.47(m,4H). 13C NMR (101 MHz, DMSO-d6) δ 172.64, 163.93, 161.50, 161.15, 150.33, 150.27, 147.54, 143.77, 131.47, 130.68, 130.60, 124.06, 124.04, 118.96, 114.79, 114.58, 113.71, 113.50, 110.50, 101.90, 96.85, 94.81, 66.34, 58.37, 48.63. LC-MS (ESI-QQQ): m / z 370.1 (calcd. for [C20H16FNO5+H]+ 370.1). Purity>99.5% (4.35 minutes at room temperature).

[0350] Separation of enantiomers:

[0351] The chiral separation of 5, i.e., SU-056, was achieved by normal phase HPLC. Normal phase chiral HPLC analysis was performed on a Waters preparative 150Q LC system equipped with 2545 quaternary pumps, 2707 automatic sample injectors, Waters column heater modules, and 2998 photodiode array detectors. Data were collected and processed using Empower 3 software. SU-056 enantiomers were separated on a Lux Cellulose-4 [cellulose tris (4-chloro-3-benzyl carbamate), 250 × 21.2 mm (ID), 5 μm] column.

[0352] The racemic compound of 1.2g amount is dissolved among the 6mL DMSO, and then each operation injection 400 μ L.Use the isocratic elution of 50:50 of solvent A (hexane) and solvent B (ethanol) to carry out enantiomer separation.Flow velocity is set to 10 milliliters / minute, and wherein the detection wavelength is 320nm.Run time is set to 50 minutes.Column oven temperature is set to 40 ℃.By Empower 3 software, fraction collection is set to for carrying out threshold value collection in window.Define collection window pair (14.0 minutes to 22.0 minutes and 30.0 minutes to 40.0 minutes), and do not collect any peak of elution outside this window.Enantiomer 1 eluted between 14.0 minutes and 22.0 minutes, and enantiomer 2 eluted between 30.0 minutes and 40.0 minutes.Pure fractions are merged, and evaporated to dryness, to obtain the desired enantiomer.

[0353] The purity of each enantiomer was checked using an analytical column Lux Cellulose-4, 100X 4.6mm (ID), 5μm column, which was eluted with a gradient of 3:7 Hex / EtOH to 1:9 Hex / EtOH in the first 5 minutes, and then with a gradient of 1:9 Hex / EtOH to 0.5:9.5 Hex / EtOH over the next 10 minutes. In this gradient, enantiomer 1 and enantiomer 2 eluted at 4.07 minutes and 5.37 minutes, respectively. Based on HPLC analysis, the purity analysis of each enantiomer showed that the UV area purity of enantiomer 1 and enantiomer 2 was >99% and 95.7%, respectively.

[0354] It will be appreciated that the SU056 enantiomers described herein can be separated, optionally as salts, using techniques known in the art including crystallization / recrystallization, diastereoisomer formation, chiral chromatography, and enzymatic reactions.

[0355] Figure 1A 、 1B , 1C and 1D show the results of cell viability assays performed using an MTT assay in different triple-negative breast cancer cells (MDA-MB-231, MDA-MB-468, SUM159 and 4T1). Cells were plated in 96-well plates and the next day, SU056 mixture, SU056 peak 1 (D-SU056) and SU056 peak 2 (L-SU056) were added to the cells at different log doses (-12.3 to -4.3) over a 48-hour period. At the end of 48 hours, cell viability was measured using an MTT reagent.

[0356] Figure 2A and 2BFigure 2 shows the results of a tumor xenograft study of SU056 and its enantiomers in 4T1 tumor xenografts grown in BALB / c cells. Mice were injected subcutaneously with 4T1 cells, and drug treatment began three days after implantation. Mice were administered vehicle (40% PEG saline) or SU056, SU056 Peak 1, and SU056 Peak 2 (50 mg / kg) via oral gavage. A) Changes in tumor volume (4T1) over time. B) Changes in body weight (4T1) over time.

Claims

1. A composition comprising (S)-9-(3-fluorophenyl)-5-(2-hydroxyethyl)-6,9-dihydro-[1,3]dioxacyclo[4,5-g]furo[3,4-b]quinolin-8(5H)-one or a pharmaceutically acceptable salt, cocrystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable precursor thereof. A pharmaceutically acceptable salt, co-crystal, ester, solvate, hydrate, isomer (including optical isomers, racemates or other mixtures thereof), tautomer, isotope, polymorph or pharmaceutically acceptable prodrug thereof, or (R)-9-(3-fluorophenyl)-5-(2-hydroxyethyl)-6,9-dihydro-[1,3]dioxacyclo[4,5-g]furo[3,4-b]quinolin-8(5H)-one in enantiomeric excess.

2. A composition according to claim 1, wherein the enantiomeric excess is at least 95%.

3. The composition of claim 1, wherein the enantiomeric excess is at least 99%.

4. The composition of claim 1, wherein the enantiomeric excess is at least 99.9%.

5. A pharmaceutical composition comprising a pharmaceutically effective amount of the composition according to claim 1 and a pharmaceutically acceptable carrier or excipient. 6 . A method for treating cancer expressing YB1 protein in a subject, the method comprising administering a pharmaceutically effective amount of the composition according to any one of claims 1 to 19 to the subject in need thereof.

7. The method of claim 7, wherein the cancer expressing the YB1 protein is selected from the group consisting of ovarian cancer, endometrial cancer, fallopian tube cancer and cervical cancer, breast cancer, lung cancer, prostate cancer, colorectal cancer, bladder cancer, melanoma, liver cancer, multiple myeloma, soft tissue sarcoma, osteosarcoma, Ewing's sarcoma, glioblastoma, acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, lymphoma, kidney cancer, renal cell carcinoma, osteosarcoma, pancreatic cancer, head and neck cancer, nasopharyngeal carcinoma and gastric cancer. 8 . The method of claim 8 , wherein the subject's cancer expressing YB1 (YBX1) protein is ovarian cancer, and the method further comprises administering a pharmaceutically effective amount of a taxane compound or a pharmaceutically acceptable salt thereof to the subject in need thereof.

9. The method of claim 9, wherein the taxane compound is selected from the group consisting of paclitaxel, docetaxel and cabazitaxel or a pharmaceutically acceptable salt thereof.

10. The method of claim 9, wherein the taxane compound is paclitaxel or a pharmaceutically acceptable salt thereof.

11. The method of claim 9, wherein the cancer in question is resistant to treatment with one or more agents from the group consisting of cisplatin, carboplatin, oxaliplatin, nedaplatin, lobaplatin, triplatin tetranitrate, and picoplatin.

12. The method of claim 8, wherein the subject's cancer expressing YB1 (YBX1) protein is breast cancer, and the method further comprises administering a pharmaceutically effective amount of a taxane compound or a pharmaceutically acceptable salt thereof to the subject in need thereof.

13. The method of claim 8, wherein the subject's cancer expressing YB1 (YBX1) protein is breast cancer, the method further comprising administering to the subject in need thereof a pharmaceutically effective amount of one or more anticancer agents selected from the group consisting of doxorubicin, pegylated liposomal doxorubicin, epirubicin, paclitaxel, docetaxel, 5-fluorouracil, capecitabine, cyclophosphamide and carboplatin or a pharmaceutically acceptable salt thereof.

14. The method of claim 8, wherein the subject's cancer expressing YB1 (YBX1) protein is breast cancer, and the method further comprises administering to the subject in need thereof a pharmaceutically effective amount of one or more anticancer agents selected from the group consisting of paclitaxel, nab-paclitaxel, docetaxel, doxorubicin, pegylated liposomal doxorubicin, epirubicin, cisplatin, carboplatin, vinorelbine, capecitabine, gemcitabine, ixabepilone and eribulin or a pharmaceutically acceptable salt thereof.

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