Combination therapy using FABP5 inhibitors with taxanes for the treatment of cancer

Abstract

The present invention provides a method for treating a subject suffering from cancer, comprising periodically administering to the subject an amount of a FABP5 inhibitor and an amount of an anti-cancer therapy, wherein these amounts, when taken together, are effective to treat the subject. The present invention also provides a FABP5 inhibitor for use as an additional therapy, in combination with an anti-cancer therapy, or in the treatment of a subject suffering from cancer. The present invention also provides the use of a FABP5 inhibitor in the manufacture of a medicament for use in the treatment of a subject suffering from cancer, in combination with or as an add-on to an anti-cancer therapy, wherein the FABP5 inhibitor and the anti-cancer therapy are administered simultaneously, contemporaneously, or concomitantly. The present invention also provides a pharmaceutical composition comprising an amount of a FABP5 inhibitor and an amount of an anti-cancer therapy for use in the treatment of cancer.

Description

[Technical Field]

[0001] This application claims priority to U.S. Provisional Patent Application No. 62 / 940,006, filed November 25, 2019, the contents of which are incorporated herein by reference.

[0002] Throughout this application, certain publications are referenced in parentheses. Full citations for these publications can be found immediately before the claims. The disclosures of these publications in their entireties are incorporated by reference into this application in order to more fully describe the state of the art to which this invention pertains. [Background technology]

[0003] Despite advances in antiandrogen and chemotherapeutic interventions, prostate cancer (PCa) remains the second leading cause of cancer-related deaths among men in the United States (Bray, F. et al. 2018). Following antiandrogen therapy, metastatic PCa often becomes castration-resistant and incurable, highlighting the need to develop next-generation therapies to treat aggressive metastatic PCa (Frieling, JS et al. 2015). Prostate adenocarcinoma utilizes lipids to promote its growth, and dysregulation of lipid metabolism is observed in PCa (Deep, G. & Schlaepfer, I. 2016; Zadra, G. et al. 2013). The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ), which regulates the expression of pro-angiogenic genes, is overexpressed in metastatic prostate cancer and is associated with reduced patient survival (Forootan, FS et al. 2014;Ahmad, I. et al. 2016;Bao, Z. et al. 2013).

[0004] Fatty acid binding protein 5 (FABP5) is a member of a class of intracellular lipid chaperones that transports fatty acids to PPARγ, leading to increased expression of pro-angiogenic factors, including vascular endothelial growth factor, which can result in a metastatic phenotype (Forootan, FS et al. 2014;Morgan, EA et al. 2008;Forootan, FS et al. 2016;Adamson, J. et al. 2003;Furuhashi, M. & Hotamisligil, GS 2008;Jing, C. et al. 2000). Normal prostate lacks FABP5 expression, but it is significantly upregulated in PCa. The degree of upregulation correlates with increasing Gleason score, and advanced metastatic prostate tumors have been shown to express the highest levels of FABP5 (Forootan, FS et al. 2014; Morgan, EA et al. 2008; Jing, C. et al. 2000; Fujita, K. et al. 2017). Reflecting this expression pattern, PCa cell lines with low metastatic potential lack FABP5 expression, while highly metastatic PCa cell lines demonstrate elevated levels of FABP5 expression (Forootan, FS et al. 2014; Kawaguchi, K. et al. 2016). Introducing FABP5 into low-metastatic PCa cell lines enhances cell migration, invasion, and tumor formation, whereas inhibiting it in highly metastatic PCa cell lines attenuates these characteristics (Bao, Z. et al. 2013; Forootan, FS et al. 2016; Kawaguchi, K. et al. 2016), positioning FABP5 as a potential therapeutic target for treating PCa.

[0005] Herein, we show that FABP5 inhibitors enhance the cytotoxic and tumor-suppressive effects of antitumor therapies.

[0006] Combination therapy The administration of two drugs to treat a given condition, such as cancer, raises several potential problems. The in vivo interactions between two drugs are complex. The effectiveness of any single drug is related to its absorption, distribution, and elimination. When two drugs are introduced into the body, each drug can affect the absorption, distribution, and elimination of the other drug, thereby altering the effectiveness of the other drug. For example, one drug may inhibit, activate, or induce the production of enzymes involved in the metabolic pathway of the other drug's elimination (Guidance for Industry, 1999). In one example, experimental studies have shown that the combined administration of fingolimod and interferon (IFN) suppresses the clinical efficacy of either treatment (Brod, 2000). Another study reported that the addition of prednisone in combination therapy with IFN-β weakened its upregulatory effect. Therefore, when two drugs are administered to treat the same condition, it is unpredictable whether each will complement, have no effect on, or interfere with the therapeutic activity of the other in human subjects.

[0007] Interactions between two drugs can not only affect the intended therapeutic activity of each drug, but can also increase the levels of toxic metabolites (Guidance for Industry, 1999). Interactions can also increase or decrease the side effects of each drug. Therefore, when administering two drugs to treat a disease, it is unpredictable what changes may occur in the negative profile of each drug. In one example, the combination of natalizumab and interferon beta-1a was observed to increase the risk of unexpected side effects (Vollmer, 2008; Rudick, 2006; Kleinschmidt-DeMasters, 2005; Langer-Gould, 2005).

[0008] Furthermore, it is difficult to accurately predict when the effects of an interaction between two drugs will become apparent. For example, a metabolic interaction between drugs may become apparent upon initial administration of the second drug, after the two have reached steady-state concentrations, or when one of the drugs is discontinued (Guidance for Industry, 1999).

[0009] Therefore, in the prior art at the time of filing, the efficacy of a combination therapy of two drugs, particularly a FABP5 inhibitor and a taxane such as docetaxel or cabazitaxel, cannot be predicted until the results of combination studies are obtained. Summary of the Invention [Means for solving the problem]

[0010] The present invention provides a method of treating a subject suffering from cancer, comprising periodically administering to the subject an amount of a FABP5 inhibitor and an amount of an anti-cancer therapy, which amounts, when taken together, are effective to treat the subject.

[0011] The present invention also provides FABP5 inhibitors for use as an additional therapy or in combination with an anti-cancer therapy or in the treatment of a subject suffering from cancer.

[0012] The present invention also provides the use of a FABP5 inhibitor in the manufacture of a medicament for use in combination with or as an add-on to an anti-cancer therapy in the treatment of a subject suffering from cancer, wherein the FABP5 inhibitor and the anti-cancer therapy are administered simultaneously, contemporaneously or concomitantly.

[0013] The present invention also provides a pharmaceutical composition comprising an amount of a FABP5 inhibitor and an amount of an anti-cancer therapy for use in treating a subject suffering from cancer, wherein the FABP5 inhibitor and the anti-cancer therapy are administered sequentially or simultaneously. [Brief explanation of the drawings]

[0014] [Figure 1]Structure and in vitro affinity (Ki, μM) of SBFI-102 / SBFI-103 and structures of docetaxel / cabazitaxel. Chemical structures and Ki values ​​of (A) SBFI-102 and (B) SBFI-103 are shown (Yan et al. 2018). Chemical structures of (C) docetaxel and (D) cabazitaxel. [Figure 2] Cytotoxicity of SBFI-102 (Figure 2A) and SBFI-103 (Figure 2B) in PC3, DU-145, 22Rv1, RWPE-1, and WI-38 cells (n≧3). SBFI-102 (Figure 2A) caused cytotoxicity in PC3, DU-145, 22Rv1, RWPE-1, and WI-38 cells with IC50 values ​​of 11.4, 8.9, 10.1, 26.0, and 29.4 μM, respectively (n≧3). SBFI-103 (Figure 2B) caused cytotoxicity in PC3, DU-145, 22Rv1, RWPE-1, and WI-38 cells with IC50 values ​​of 6.3, 3.3, 3.1, 20.6, and 29.6 μM, respectively (n≧3). [Figure 3] Cytotoxicity of docetaxel in PC3, DU-145, and 22Rv1 cells. Docetaxel caused cytotoxicity in (A) PC3, (B) DU-145, and (C) 22Rv1 cells with IC50 values ​​of 1.9, 0.8, and 0.3 nM, respectively (n≧3). IC50 is the half-maximal inhibitory concentration. [Figure 4] Cytotoxicity of cabazitaxel in PC3, DU-145, and 22Rv1 cells. Cabazitaxel caused cytotoxicity in (A) PC3, (B) DU-145, and (C) 22Rv1 cells with IC50 values ​​of 1.6, 0.2, and 0.3 nM, respectively (n≧3). IC50 is the half-maximal inhibitory concentration. [Figure 5]Cytotoxicity of PC3, DU-145, and 22Rv1 cells after combined treatment with docetaxel and SBFI-102 or SBFI-103. A) Cytotoxicity of PC3 cells incubated with docetaxel in the presence of SBFI-102, or B) SBFI-103 (n≧3). C) Cytotoxicity of DU-145 cells incubated with docetaxel in the presence of SBFI-102, or D) SBFI-103 (n≧3). E) Cytotoxicity of 22Rv1 cells incubated with docetaxel in the presence of SBFI-102, or F) SBFI-103 (n≧3). [Figure 6] Cytotoxicity of PC3, DU-145, and 22Rv1 cells after combined treatment with cabazitaxel and SBFI-102 or SBFI-103. A) Cytotoxicity of PC3 cells incubated with cabazitaxel in the presence of SBFI-102, or B) SBFI-103 (n≧3). C) Cytotoxicity of DU-145 cells incubated with cabazitaxel in the presence of SBFI-102, or D) SBFI-103 (n≧3). E) Cytotoxicity of 22Rv1 cells incubated with cabazitaxel in the presence of SBFI-102, or F) SBFI-103 (n≧3). [Figure 7] Inhibition of subcutaneous tumor growth by docetaxel or FABP5 inhibitors. PC3 cells (1 × 10) were implanted subcutaneously into male BALB / c nude mice. From day 15 onward, mice were treated with vehicle, SBFI-102 (20 mg / kg daily), SBFI-103 (20 mg / kg daily), or docetaxel (5 mg / kg or 10 mg / kg weekly). A) Tumor growth over time of treatment. B–D) Tumor volume on days 25, 30, and 35, respectively. *P < .05 (vs. vehicle treatment); **P < .01 (vs. vehicle treatment); ***P < .001 (vs. vehicle treatment); #P < .05 (vs. 10 mg / kg docetaxel treatment); ♯♯P < .01 (vs. 10 mg / kg docetaxel treatment); (n = 5). [Figure 8]Inhibition of subcutaneous tumor growth by docetaxel and FABP5 inhibitors. PC3 cells (1 × 10) were implanted subcutaneously into male BALB / c nude mice. From day 15 onward, mice were treated with vehicle, a combination of SBFI-102 (20 mg / kg daily) and docetaxel (5 mg / kg weekly), a combination of SBFI-103 (20 mg / kg daily) and docetaxel (5 mg / kg weekly), or docetaxel (5 mg / kg or 10 mg / kg weekly). A) Tumor growth over time of treatment. B–D) Tumor volume on days 25, 30, and 35, respectively. **P < .01 (vs. vehicle treatment); ***P < .001 (vs. vehicle treatment); #P < .05 (vs. 10 mg / kg docetaxel treatment); NS (vs. 10 mg / kg docetaxel treatment); (n = 5). DETAILED DESCRIPTION OF THE INVENTION

[0015] The present invention provides a method of treating cancer in a subject, the method comprising administering to the subject an effective amount of a FABP5 inhibitor in conjunction with an anti-cancer therapy.

[0016] The present invention also provides a method comprising periodically administering to a subject amounts of a FABP5 inhibitor and an anti-cancer therapy, which amounts, when taken together, are effective to treat the subject.

[0017] In an embodiment, the amount of the FABP5 inhibitor and the amount of the anti-cancer therapy, when administered together, are more effective to treat a subject than when the same amount of each agent is administered alone.

[0018] In an embodiment, the subject has undergone anti-cancer therapy prior to initiation of FABP5 inhibitor therapy.

[0019] In an embodiment, the subject is receiving FABP5 inhibitor therapy prior to the initiation of anti-cancer therapy.

[0020] In an embodiment, the FABP5 inhibitor and the anti-cancer therapy are administered sequentially.

[0021] In an embodiment, the FABP5 inhibitor is administered first, followed by the anti-cancer therapy.

[0022] In embodiments, the anti-cancer therapy is administered first, followed by the FABP5 inhibitor.

[0023] In an embodiment, the FABP5 inhibitor and the anti-cancer therapy are administered simultaneously.

[0024] In an embodiment, the FABP5 inhibitor is administered orally. In an embodiment, the FABP5 inhibitor is administered intravenously. In an embodiment, the FABP5 inhibitor is administered intraperitoneally.

[0025] In an embodiment, the anti-cancer therapy is a taxane.

[0026] In embodiments, the taxane is administered intravenously. In embodiments, the taxane is administered intraperitoneally.

[0027] In an embodiment, the cancer expresses FABP5.

[0028] In an embodiment, the cancer overexpresses FABP5.

[0029] In an embodiment, the cancer is prostate cancer. In an embodiment, the cancer is skin cancer. In an embodiment, the cancer is breast cancer. In an embodiment, the cancer is hepatocellular carcinoma. In an embodiment, the cancer is cervical cancer.

[0030] In a preferred embodiment, the cancer is prostate cancer. In another preferred embodiment, the cancer is drug-resistant prostate cancer. In another preferred embodiment, the cancer is metastatic prostate cancer.

[0031] In embodiments, the FABP5 inhibitor has the structure: [ka] (In the formula, R1 and R2 are different and each represent -C(=O)R 13 , -C(=O)OR 13 , -C(=O)O-alkyl-R 13 , -C(=O)NR 13 R 14 , -Alkyl-C(=O)R 13 , -Alkyl-C(=O)OR 13 , -Alkyl-C(=O)NR 13 R 14 , -Alkyl-OC(=O)OR 13 , -alkyl-OC(=O)R 13 , -alkyl-OR 13 , -alkyl-NR 13 R 14 , -alkyl-NHC(=O)R 13 , -Alkyl-NHC(=O)OR 13 , -alkyl-NHC(=O)R 13 , -Alkyl-NHC(=O)NR 13 R 14 , -Alkyl-NHC(=S)NR 13 R 14 , -Alkyl-NHC(=NR 13 )NR 13 R 14 , -C(-OH)C(=O)OR 13 , -C(=O)C(=O)OR 13 or -C=CR 13 and where R 13 and R 14 are each independently H, CF3, or C 1~10 Alkyl, C 2~10 Alkenyl, C 2~10 alkynyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, heterocyclyl, or joined to form a cycloalkyl or heterocyclyl; R3, R4, R5, R6, R7, R8, R9, R 10 , R 11 and R 12 are each independently H, halogen, -NO2, -CN, or -NHR 15 , -NR 15 R16 , -SR 15 , -SO2R 15 , -OR 15 , -CO2R 15 , CF3, -Alkyl-NR 15 R 16 , -alkyl-OR 15 , C 1~10 Alkyl, C 2~10 Alkenyl, C 2~10 alkynyl, aryl, heteroaryl, or heterocyclyl; where R 15 and R 16 are each independently H, CF3, or C 1~10 Alkyl, C 2~10 Alkenyl, C 2~10 alkynyl, heteroalkyl, cycloheteroalkyl, aryl, heteroaryl, or heterocyclyl or an enantiomer or racemate thereof; or a pharmaceutically acceptable salt thereof.

[0032] In embodiments, the compound has structure I [ka] or an enantiomer or racemate thereof; or a pharmaceutically acceptable salt thereof, wherein R1 and R2 are different and each represent -C(=O)R 13 , -C(=O)OR 13 , -C(=O)O-alkyl-R 13 , -C(=O)NR 13 R 14 , -Alkyl-C(=O)R 13 , -Alkyl-C(=O)OR 13 , -Alkyl-C(=O)NR 13 R 14 , -Alkyl-OC(=O)OR 13 , -alkyl-OC(=O)R 13 , -alkyl-OR 13 , -alkyl-NR 13 R 14 , -alkyl-NHC(=O)R 13, -Alkyl-NHC(=O)OR 13 , -alkyl-NHC(=O)R 13 , -Alkyl-NHC(=O)NR 13 R 14 , -Alkyl-NHC(=S)NR 13 R 14 , -Alkyl-NHC(=NR 13 )NR 13 R 14 , -C(-OH)C(=O)OR 13 , -C(=O)C(=O)OR 13 or -C=CR 13 and where R 13 and R 14 are each independently H, CF3, or C 1~10 Alkyl, C 2~10 Alkenyl, C 2~10 alkynyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, heterocyclyl, or joined to form a cycloalkyl or heterocyclyl; R3, R4, R5, R6, R7, R8, R9, R 10 , R 11 and R 12 are each independently H, halogen, -NO2, -CN, or -NHR 15 , -NR 15 R 16 , -SR 15 , -SO2R 15 , -OR 15 , -CO2R 15 , CF3, -Alkyl-NR 15 R 16 , -alkyl-OR 15 , C 1~10 Alkyl, C 2~10 Alkenyl, C 2~10 alkynyl, aryl, heteroaryl, or heterocyclyl; where R 15 and R 16 are each independently H, CF3, or C 1~10 Alkyl, C 2~10 Alkenyl, C 2~10It is alkynyl, heteroalkyl, cycloheteroalkyl, aryl, heteroaryl or heterocyclyl.

[0033] In embodiments, the compound has structure II [ka] or an enantiomer or racemate thereof; or a pharmaceutically acceptable salt thereof, wherein R1 and R2 are different and each represent -C(=O)R 13 , -C(=O)OR 13 , -C(=O)O-alkyl-R 13 , -C(=O)NR 13 R 14 , -Alkyl-C(=O)R 13 , -Alkyl-C(=O)OR 13 , -Alkyl-C(=O)NR 13 R 14 , -Alkyl-OC(=O)OR 13 , -alkyl-OC(=O)R 13 , -alkyl-OR 13 , -alkyl-NR 13 R 14 , -alkyl-NHC(=O)R 13 , -Alkyl-NHC(=O)OR 13 , -alkyl-NHC(=O)R 13 , -Alkyl-NHC(=O)NR 13 R 14 , -Alkyl-NHC(=S)NR 13 R 14 , -Alkyl-NHC(=NR 13 )NR 13 R 14 , -C(-OH)C(=O)OR 13 , -C(=O)C(=O)OR 13 or -C=CR 13 and where R 13 and R 14 are each independently H, CF3, or C 1~10 Alkyl, C 2~10 Alkenyl, C 2~10alkynyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, heterocyclyl, or joined to form a cycloalkyl or heterocyclyl; R3, R4, R5, R6, R7, R8, R9, R 10 , R 11 and R 12 are each independently H, halogen, -NO2, -CN, or -NHR 15 , -NR 15 R 16 , -SR 15 , -SO2R 15 , -OR 15 , -CO2R 15 , CF3, -Alkyl-NR 15 R 16 , -alkyl-OR 15 , C 1~10 Alkyl, C 2~10 Alkenyl, C 2~10 alkynyl, aryl, heteroaryl, or heterocyclyl; where R 15 and R 16 are each independently H, CF3, or C 1~10 Alkyl, C 2~10 Alkenyl, C 2~10 It is alkynyl, heteroalkyl, cycloheteroalkyl, aryl, heteroaryl or heterocyclyl.

[0034] In embodiments, the FABP5 inhibitor has the structure: [ka] or a pharmaceutically acceptable salt thereof.

[0035] In embodiments, the taxane is paclitaxel, docetaxel, or cabazitaxel. In preferred embodiments, the taxane is docetaxel or cabazitaxel. In another preferred embodiment, the taxane is docetaxel. In another preferred embodiment, the taxane is cabazitaxel.

[0036] In embodiments, the anti-cancer therapy is radiation therapy.

[0037] In one embodiment, the radiation therapy is external beam radiation, hi another embodiment, the radiation therapy is brachytherapy.

[0038] In an embodiment, the subject is a mammal.

[0039] The present invention provides a pharmaceutical composition comprising a FABP5 inhibitor and a pharmaceutically acceptable carrier.

[0040] In embodiments, the pharmaceutical composition of the FABP5 inhibitor has the structure: [ka] (In the formula, R1 and R2 are different and each represent -C(=O)R 13 , -C(=O)OR 13 , -C(=O)O-alkyl-R 13 , -C(=O)NR 13 R 14 , -Alkyl-C(=O)R 13 , -Alkyl-C(=O)OR 13 , -Alkyl-C(=O)NR 13 R 14 , -Alkyl-OC(=O)OR 13 , -alkyl-OC(=O)R 13 , -alkyl-OR 13 , -alkyl-NR 13 R 14 , -alkyl-NHC(=O)R 13 , -Alkyl-NHC(=O)OR 13 , -alkyl-NHC(=O)R 13 , -Alkyl-NHC(=O)NR 13 R 14 , -Alkyl-NHC(=S)NR 13 R 14 , -Alkyl-NHC(=NR 13 )NR 13 R 14 , -C(-OH)C(=O)OR 13, -C(=O)C(=O)OR 13 or -C=CR 13 and where R 13 and R 14 are each independently H, CF3, or C 1~10 Alkyl, C 2~10 Alkenyl, C 2~10 alkynyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, heterocyclyl, or joined to form a cycloalkyl or heterocyclyl; R3, R4, R5, R6, R7, R8, R9, R 10 , R 11 and R 12 are each independently H, halogen, -NO2, -CN, or -NHR 15 , -NR 15 R 16 , -SR 15 , -SO2R 15 , -OR 15 , -CO2R 15 , CF3, -Alkyl-NR 15 R 16 , -alkyl-OR 15 , C 1~10 Alkyl, C 2~10 Alkenyl, C 2~10 alkynyl, aryl, heteroaryl, or heterocyclyl; where R 15 and R 16 are each independently H, CF3, or C 1~10 Alkyl, C 2~10 Alkenyl, C 2~10 alkynyl, heteroalkyl, cycloheteroalkyl, aryl, heteroaryl, or heterocyclyl It has.

[0041] In the above embodiment, the compound of the pharmaceutical composition has the structure I [ka] or an enantiomer or racemate thereof; or a pharmaceutically acceptable salt thereof, wherein R1 and R2 are different and each represent -C(=O)R 13 , -C(=O)OR 13 , -C(=O)O-alkyl-R 13 , -C(=O)NR 13 R 14 , -Alkyl-C(=O)R 13 , -Alkyl-C(=O)OR 13 , -Alkyl-C(=O)NR 13 R 14 , -Alkyl-OC(=O)OR 13 , -alkyl-OC(=O)R 13 , -alkyl-OR 13 , -alkyl-NR 13 R 14 , -alkyl-NHC(=O)R 13 , -Alkyl-NHC(=O)OR 13 , -alkyl-NHC(=O)R 13 , -Alkyl-NHC(=O)NR 13 R 14 , -Alkyl-NHC(=S)NR 13 R 14 , -Alkyl-NHC(=NR 13 )NR 13 R 14 , -C(-OH)C(=O)OR 13 , -C(=O)C(=O)OR 13 or -C=CR 13 and where R 13 and R 14 are each independently H, CF3, or C 1~10 Alkyl, C 2~10 Alkenyl, C 2~10 alkynyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, heterocyclyl, or joined to form a cycloalkyl or heterocyclyl; R3, R4, R5, R6, R7, R8, R9, R 10 , R 11 and R 12 are each independently H, halogen, -NO2, -CN, or -NHR 15 , -NR 15 R16 , -SR 15 , -SO2R 15 , -OR 15 , -CO2R 15 , CF3, -Alkyl-NR 15 R 16 , -alkyl-OR 15 , C 1~10 Alkyl, C 2~10 Alkenyl, C 2~10 alkynyl, aryl, heteroaryl, or heterocyclyl; where R 15 and R 16 are each independently H, CF3, or C 1~10 Alkyl, C 2~10 Alkenyl, C 2~10 It is alkynyl, heteroalkyl, cycloheteroalkyl, aryl, heteroaryl or heterocyclyl.

[0042] In the above embodiment, the compound of the pharmaceutical composition has the structure II [ka] or an enantiomer or racemate thereof; or a pharmaceutically acceptable salt thereof, wherein R1 and R2 are different and each represent -C(=O)R 13 , -C(=O)OR 13 , -C(=O)O-alkyl-R 13 , -C(=O)NR 13 R 14 , -Alkyl-C(=O)R 13 , -Alkyl-C(=O)OR 13 , -Alkyl-C(=O)NR 13 R 14 , -Alkyl-OC(=O)OR 13 , -alkyl-OC(=O)R 13 , -alkyl-OR 13 , -alkyl-NR 13 R 14 , -alkyl-NHC(=O)R 13 , -Alkyl-NHC(=O)OR 13 , -alkyl-NHC(=O)R13 , -Alkyl-NHC(=O)NR 13 R 14 , -Alkyl-NHC(=S)NR 13 R 14 , -Alkyl-NHC(=NR 13 )NR 13 R 14 , -C(-OH)C(=O)OR 13 , -C(=O)C(=O)OR 13 or -C=CR 13 and where R 13 and R 14 are each independently H, CF3, or C 1~10 Alkyl, C 2~10 Alkenyl, C 2~10 alkynyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, heterocyclyl, or joined to form a cycloalkyl or heterocyclyl; R3, R4, R5, R6, R7, R8, R9, R 10 , R 11 and R 12 are each independently H, halogen, -NO2, -CN, or -NHR 15 , -NR 15 R 16 , -SR 15 , -SO2R 15 , -OR 15 , -CO2R 15 , CF3, -Alkyl-NR 15 R 16 , -alkyl-OR 15 , C 1~10 Alkyl, C 2~10 Alkenyl, C 2~10 alkynyl, aryl, heteroaryl, or heterocyclyl; where R 15 and R 16 are each independently H, CF3, or C 1~10 Alkyl, C 2~10 Alkenyl, C 2~10 It is alkynyl, heteroalkyl, cycloheteroalkyl, aryl, heteroaryl or heterocyclyl.

[0043] In embodiments, the pharmaceutical composition of the FABP5 inhibitor has the structure: [ka] It has.

[0044] In the above embodiment, the pharmaceutical composition further comprises a taxane.

[0045] In the above embodiment, the pharmaceutical composition comprises docetaxel. In another above embodiment, the pharmaceutical composition comprises cabazitaxel.

[0046] The present invention also provides the use of a FABP5 inhibitor in combination with or as an add-on to an anti-cancer therapy in the treatment of a subject suffering from cancer, wherein the FABP5 inhibitor and the anti-cancer therapy are administered simultaneously, contemporaneously, or concomitantly.

[0047] In the above embodiments, the FABP5 inhibitor has the structure: [ka] (In the formula, R1 and R2 are different and each represent -C(=O)R 13 , -C(=O)OR 13 , -C(=O)O-alkyl-R 13 , -C(=O)NR 13 R 14 , -Alkyl-C(=O)R 13 , -Alkyl-C(=O)OR 13 , -Alkyl-C(=O)NR 13 R 14 , -Alkyl-OC(=O)OR 13 , -alkyl-OC(=O)R 13 , -alkyl-OR 13 , -alkyl-NR 13 R 14 , -alkyl-NHC(=O)R 13 , -Alkyl-NHC(=O)OR 13 , -alkyl-NHC(=O)R13 , -Alkyl-NHC(=O)NR 13 R 14 , -Alkyl-NHC(=S)NR 13 R 14 , -Alkyl-NHC(=NR 13 )NR 13 R 14 , -C(-OH)C(=O)OR 13 , -C(=O)C(=O)OR 13 or -C=CR 13 and where R 13 and R 14 are each independently H, CF3, or C 1~10 Alkyl, C 2~10 Alkenyl, C 2~10 alkynyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, heterocyclyl, or joined to form a cycloalkyl or heterocyclyl; R3, R4, R5, R6, R7, R8, R9, R 10 , R 11 and R 12 are each independently H, halogen, -NO2, -CN, or -NHR 15 , -NR 15 R 16 , -SR 15 , -SO2R 15 , -OR 15 , -CO2R 15 , CF3, -Alkyl-NR 15 R 16 , -alkyl-OR 15 , C 1~10 Alkyl, C 2~10 Alkenyl, C 2~10 alkynyl, aryl, heteroaryl, or heterocyclyl; where R 15 and R 16 are each independently H, CF3, or C 1~10 Alkyl, C 2~10 Alkenyl, C 2~10 alkynyl, heteroalkyl, cycloheteroalkyl, aryl, heteroaryl, or heterocyclyl or an enantiomer or racemate thereof; or a pharmaceutically acceptable salt thereof.

[0048] In the above embodiment, the anti-cancer therapy is a taxane.

[0049] In the above embodiment, the anti-cancer therapy is radiation therapy.

[0050] In the above embodiment, the cancer is prostate cancer.

[0051] The present invention also provides the use of a FABP5 inhibitor in the manufacture of a medicament for use in combination with or as an add-on to an anti-cancer therapy in the treatment of a subject suffering from cancer, wherein the FABP5 inhibitor and the anti-cancer therapy are administered simultaneously, contemporaneously or concomitantly.

[0052] The present invention also provides a pharmaceutical composition comprising an amount of a FABP5 inhibitor and an amount of an anti-cancer therapy for use in treating a subject suffering from cancer, wherein the FABP5 inhibitor and the anti-cancer therapy are administered simultaneously, contemporaneously, or concomitantly.

[0053] In an embodiment of the above pharmaceutical composition, the FABP5 inhibitor has the structure: [ka] (In the formula, R1 and R2 are different and each represent -C(=O)R 13 , -C(=O)OR 13 , -C(=O)O-alkyl-R 13 , -C(=O)NR 13 R 14 , -Alkyl-C(=O)R 13 , -Alkyl-C(=O)OR 13 , -Alkyl-C(=O)NR 13 R 14 , -Alkyl-OC(=O)OR 13 , -alkyl-OC(=O)R 13 , -alkyl-OR 13, -alkyl-NR 13 R 14 , -alkyl-NHC(=O)R 13 , -Alkyl-NHC(=O)OR 13 , -alkyl-NHC(=O)R 13 , -Alkyl-NHC(=O)NR 13 R 14 , -Alkyl-NHC(=S)NR 13 R 14 , -Alkyl-NHC(=NR 13 )NR 13 R 14 , -C(-OH)C(=O)OR 13 , -C(=O)C(=O)OR 13 or -C=CR 13 and where R 13 and R 14 are each independently H, CF3, or C 1~10 Alkyl, C 2~10 Alkenyl, C 2~10 alkynyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, heterocyclyl, or joined to form a cycloalkyl or heterocyclyl; R3, R4, R5, R6, R7, R8, R9, R 10 , R 11 and R 12 are each independently H, halogen, -NO2, -CN, or -NHR 15 , -NR 15 R 16 , -SR 15 , -SO2R 15 , -OR 15 , -CO2R 15 , CF3, -Alkyl-NR 15 R 16 , -alkyl-OR 15 , C 1~10 Alkyl, C 2~10 Alkenyl, C 2~10 alkynyl, aryl, heteroaryl, or heterocyclyl; where R 15 and R 16 are each independently H, CF3, or C 1~10Alkyl, C 2~10 Alkenyl, C 2~10 alkynyl, heteroalkyl, cycloheteroalkyl, aryl, heteroaryl, or heterocyclyl or an enantiomer or racemate thereof; or a pharmaceutically acceptable salt thereof.

[0054] In an embodiment of the above pharmaceutical composition, the anti-cancer therapy is a taxane.

[0055] In an embodiment of the above pharmaceutical composition, the anti-cancer therapy is radiation therapy.

[0056] In an embodiment of the above pharmaceutical composition, the cancer is prostate cancer.

[0057] Another embodiment relates to a method for treating or preventing cancer, comprising administering a therapeutically effective amount of a FABP5 inhibitor in combination with a taxane to a patient in need thereof. Another embodiment relates to a method for treating or preventing cancer, comprising administering a therapeutically effective amount of a pharmaceutical composition comprising a FABP5 inhibitor and a taxane to a patient in need thereof. Another embodiment relates to a method for treating cancer, comprising administering a therapeutically effective amount of SBFI-102 in combination with a taxane to a patient in need thereof. Another embodiment relates to a method for treating cancer, comprising administering a therapeutically effective amount of a pharmaceutical composition comprising SBFI-102 and a taxane to a patient in need thereof. Another embodiment relates to a method for treating cancer, comprising administering a therapeutically effective amount of SBFI-103 in combination with a taxane to a patient in need thereof. Another embodiment relates to a method for treating cancer, comprising administering a therapeutically effective amount of a pharmaceutical composition comprising SBFI-103 and a taxane to a patient in need thereof.

[0058] In certain embodiments, a method of treating cancer comprises administering to a patient in need thereof a therapeutically effective amount of a FABP5 inhibitor in combination with a taxane.

[0059] In certain embodiments, a method of treating cancer comprises administering to a patient in need thereof a therapeutically effective amount of SBFI-102 or SBFI-103 in combination with a taxane.

[0060] In certain embodiments, a method of treating cancer comprises administering to a patient in need thereof a therapeutically effective amount of a FABP5 inhibitor in combination with docetaxel or cabazitaxel.

[0061] In certain embodiments, a method of treating cancer comprises administering to a patient in need thereof a therapeutically effective amount of SBFI-102 or SBFI-103 in combination with docetaxel or cabazitaxel.

[0062] In the above embodiments, the combination of a FABP5 inhibitor and a taxane results in a synergistic anti-cancer effect.In the above embodiments, the combination of a FABP5 inhibitor and a taxane results in an additive anti-cancer effect.

[0063] According to further embodiments, the above methods are used in the treatment of prostate cancer. According to further embodiments, the above methods are used in the treatment of drug-resistant prostate cancer.

[0064] Taxanes, such as docetaxel and cabazitaxel, are utilized in standard treatment regimens for chemotherapy-naive castration-resistant prostate cancer. However, tumors often develop resistance to taxane chemotherapy. In one embodiment, the combination of a FABP5 inhibitor with a taxane results in delayed resistance to taxane chemotherapy. In another embodiment, the combination prevents the development of resistance to taxane chemotherapy. In one embodiment, the combination of a FABP5 inhibitor with a taxane results in delayed resistance to the FABP5 inhibitor. In another embodiment, the combination prevents the development of resistance to the FABP5 inhibitor.

[0065] In some embodiments, the combination of a FABP5 inhibitor with a taxane allows for the use of a lower dose of the taxane than would be required if the agent were used alone. In some embodiments, this combination results in a reduction in adverse effects associated with taxane therapy. In some embodiments, the combination of a FABP5 inhibitor with a taxane allows for the use of a lower dose of the FABP5 inhibitor than would be required if the agent were used alone. In some embodiments, this combination results in a reduction in adverse effects associated with FABP5 inhibitor therapy.

[0066] In embodiments, the anti-cancer activity of the FABP5 inhibitor is synergistic with the taxane.

[0067] In an embodiment, the cancer exhibits enhanced expression of FABP5.

[0068] Examples of cancers that overexpress FABP5 include, but are not limited to, prostate cancer, skin cancer, breast cancer, hepatocellular carcinoma, and cervical cancer.

[0069] In one embodiment, the compounds described herein inhibit FABP5.

[0070] In other embodiments, the subject compounds described herein can be radiolabeled.

[0071] In an embodiment, the combination therapy comprises a taxane together with a FAB5 inhibitor. In a preferred embodiment, the taxane is docetaxel. In another preferred embodiment, the taxane is cabazitaxel.

[0072] In one embodiment, the FABP5 inhibitor and the anti-cancer therapy are administered concurrently. In another embodiment, the FABP5 inhibitor and the anti-cancer therapy are administered sequentially.

[0073] In one embodiment, the FABP5 inhibitor and the anti-cancer therapy are administered simultaneously. In one embodiment, the FABP5 inhibitor and the anti-cancer therapy are administered contemporaneously. In one embodiment, the FABP5 inhibitor and the anti-cancer therapy are administered concomitantly.

[0074] In one embodiment, the FABP5 inhibitor is SBFI-102.

[0075] "SBFI-102" has the following structure: [ka] It has.

[0076] In one embodiment, the FABP5 inhibitor is SBFI-103.

[0077] "SBFI-103" has the structure: [ka] It has.

[0078] In one embodiment, the combination of a FABP5 inhibitor and a taxane results in enhanced anti-tumor efficacy in a subject. In one embodiment, the combination of a FABP5 inhibitor and a taxane results in synergistic anti-tumor efficacy in a subject.

[0079] In another embodiment, the combination of a FABP5 inhibitor and a taxane allows for the use of a lower dose of the taxane in a subject.

[0080] In another embodiment, the combination of the FABP5 inhibitor and the taxane reduces resistance to the effects of the taxane.

[0081] In another embodiment, the combination of a FABP5 inhibitor and a taxane reduces the adverse effects associated with the taxane chemotherapeutic agent.

[0082] In one embodiment, the FABP5 inhibitor enhances the cytotoxic and tumor-suppressing effects of docetaxel or cabazitaxel.

[0083] In one embodiment, the FABP5 inhibitor is administered in combination with radiation therapy.

[0084] In the above embodiment, the FABP5 inhibitor is SBFI-102.

[0085] In the above embodiment, the FABP5 inhibitor is SBFI-103.

[0086] In the above preferred embodiment, the radiation therapy is external beam radiation therapy.

[0087] In the above preferred embodiment, the radiation therapy is brachytherapy.

[0088] In one embodiment, the FABP5 inhibitor is radiolabeled. In another embodiment, SBFI-102 is radiolabeled. In another embodiment, SBFI-103 is radiolabeled.

[0089] In the above embodiments, the FABP5 inhibitor is radiolabeled with carbon-11. In another embodiment, the FABP5 inhibitor is radiolabeled with nitrogen-13. In another embodiment, the FABP5 inhibitor is radiolabeled with oxygen-15. In another embodiment, the FABP5 inhibitor is radiolabeled with fluorine-18. In another embodiment, the FABP5 inhibitor is radiolabeled with gallium-68. In another embodiment, the FABP5 inhibitor is radiolabeled with zirconium-89. In another embodiment, the FABP5 inhibitor is radiolabeled with rubidium-82. In another embodiment, the FABP5 inhibitor is radiolabeled with copper-64. In another embodiment, the FABP5 inhibitor is radiolabeled with yttrium-86. In another embodiment, the FABP5 inhibitor is radiolabeled with bromine-76. In another embodiment, the FABP5 inhibitor is radiolabeled with iodine-123. In another embodiment, the FABP5 inhibitor is radiolabeled with iodine-124. In another embodiment, the FABP5 inhibitor is radiolabeled with technetium-99. In another embodiment, the FABP5 inhibitor is radiolabeled with xenon-133. In another embodiment, the FABP5 inhibitor is radiolabeled with thallium-201.

[0090] In another embodiment, a method for radiolabeling a FABP5 inhibitor is provided. In another embodiment, a method for radiolabeling SBFI-102 is provided. In another embodiment, a method for radiolabeling SBFI-103 is provided.

[0091] The quantity of active ingredient in a unit dose preparation will vary depending on the particular application and the potency of the active ingredient and may be adjusted to 0.1 mg to 10,000 mg, more usually 1.0 mg to 1,000 mg, and most usually 10 mg to 500 mg. The compositions may also contain other compatible therapeutic agents, if desired.

[0092] The amount of FABP5 inhibitor in a unit dose preparation will vary depending on the particular application and the potency of the FABP5 inhibitor, and may be adjusted to 0.1 mg to 10,000 mg, more typically 1.0 mg to 1,000 mg, and most typically 10 mg to 500 mg. The composition may also contain other compatible therapeutic agents, if desired.

[0093] Docetaxel and cabazitaxel may be used at their approved dose levels, which are set forth in the Physician's Desk Reference (Physicians' Desk Reference, 2017), the entire contents of which are incorporated herein by reference.

[0094] Any concentration range, percentage range, or ratio range described herein should be understood to include every integer and fractional concentration, percentage, or ratio within that range, such as tenths and hundredths of the integer, unless otherwise stated.

[0095] term As used herein and unless otherwise stated, each of the following terms shall have the definition set forth below.

[0096] As used herein, the terms "administer," "administering," and "administration" refer to any method of delivering a composition to a subject to provide a therapeutic effect in sound medical practice.

[0097] As used herein, the phrase "effective amount" or "therapeutically effective amount" of an active agent or component, or equivalently herein, a pharmaceutically active agent or component, refers to a sufficient amount of a pharmaceutically active agent to have a therapeutic effect when administered. A therapeutically effective amount of a pharmaceutically active agent can be, would be, or is expected to cause relief of symptoms. An effective amount of a pharmaceutically active agent may vary depending on the particular condition or conditions being treated, the severity of the condition, the duration of treatment, the particular components of the composition being used, and similar factors.

[0098] As used herein, "subject," or "individual," or "animal," or "patient," or "mammal," refers to any subject for whom diagnosis, prognosis, or treatment is desired, particularly a mammalian subject, e.g., a human.

[0099] As used herein, "treatment" or "treating" a disease, disorder, or condition includes alleviating at least one symptom thereof, reducing its severity, or slowing, preventing, or inhibiting its progression. Treatment does not necessarily mean that the disease, disorder, or condition is completely cured. The compositions useful herein need only reduce the severity of the disease, disorder, or condition, reduce the severity of symptoms associated therewith, provide an improvement in the quality of life of the patient or subject, or delay, prevent, or inhibit the onset of the disease, disorder, or condition.

[0100] As used herein, "anti-cancer therapy" refers to any treatment to stop or prevent cancer. Types of anti-cancer therapy include, but are not limited to, chemotherapy, radiation therapy, surgery, and immunotherapy.

[0101] As used herein, the term "chemotherapy" refers to the use of any drug to treat cancer or to provide a beneficial therapeutic effect to a subject suffering from cancer.

[0102] As used herein, the term "radiotherapy" or "radiation treatment" refers to the use of ionizing radiation to control or kill cancer cells. Types of radiation therapy include, but are not limited to, external beam radiation, brachytherapy, or systemic radioisotope therapy.

[0103] Anti-cancer therapy includes a variety of therapies, both chemo- and radiation-based treatments. Chemotherapy includes, for example, cisplatin (CDDP), carboplatin, oxaliplatin, irinotecan, topotecan, procarbazine, mechlorethamine, cyclophosphamide, camptothecin, ifosfamide, melphalan, chlorambucil, busulfan, nitrosurea, dactinomycin, daunorubicin, doxorubicin, bleomycin, plicomycin, mitomycin, etoposide (VP16), tamoxifen, raloxifene, estrogen receptor binding agents, taxanes, docetaxel, paclitaxel, Abraxane®, gemcitabine, navelbine, farnesyl-protein transferase inhibitors, transplatinum, 5-fluorouracil, vincristine, vinblastine, methotrexate, medroxy-progesterone acetate, or any analog or derived variant of the above.

[0104] Other examples of chemotherapy include receptor tyrosine kinase inhibitors (RTKi), including, but not limited to, Herceptin (Genentech), Laptinib (GSK), Tarceva (Genentech / OSI), Gefitinib (AstraZenca), Fluro-Sorafenib (Bayer), Sorafenib (Bayer), PF-2341066 (Pfizer), or any analog or derived variant thereof. It is specifically contemplated that any of these compounds or derivatives or analogs may be used in these combination therapies.

[0105] Additionally, chemotherapy also includes PARP inhibitors, such as 4-(3-(4-cyclopropylcarbonyl)piperazin-4-ylcarbonyl)-4-fluorophenyl)methyl(2H)phthalazin-1-one (olaparib: AZD2281; KUO059436, AstraZeneca), 2-(2R)-2-methylpyrrolidin-2-yl)-1H-benzimidazole-4-carboxamide (ABT-888, Abbott Laboratories), benzimidazole derivatives (ABT-472, Abbott Laboratories), O-(3-piperidino-2-hydroxy-1-propyl)nicotinic acid amidoxime (BGP15, Allos Therapeutics), AZD2461 (AstraZeneca), and BMN673 (BioMarin Pharmaceuticals). Inc), 3-2-fluoro-5-(4-oxo-3,4-dihydro-phthalazin-1-ylmethyl)-phenyl-5-methyl-imidazolidine-2,4-dione, 3-3-(5,8-difluoro-4-oxo-3,4-dihydro-phthalazin-1-ylmethyl)-phenyl-5-methyl-imidazoline-2,4-dione, 5-chloro-2-1-3-(1,4)diazepane-1-carbonyl)-4-fluoro-phenyl-ethoxybenzamide, 2-3-2-fluoro-5-(4-oxo-3,4-dihydrophthalazin-1-ylmethyl)-phenyl-5-methyl-2,4-dioxoimidazolidine-1-yl )-acetamido,-4-3-(4-cyclopropanecarbonyl-piperazine-1-carbonyl)-4-fluorobenzyl-2H-phthalazin-1-one, 3-2-fluoro-5-(4-oxo-3,4,dihydro-phthalazin-1-ylmethyl)-phenyl-5,5-dimethyl-1-(2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl-imidazoline-2,4-dione, 8-fluoro-2-(4-methylaminomethyl-phenyl)-1,3,4,5-tetrahydro-azepino[5.4.3-cd]indol-6-one (WO 2008 / 020180), BSI101 (BiPar Sciences), CE9722 (Cephalon Inc), GPI21016 (Eisai Co), PARP inhibitor ROCHE (F.Hoffman La Roche Ltd), indole (INO1001, Genentech), PARP inhibitor INOTEK (Inotek Pharmaceuticals Co), (S)-2-(4-(piperidin-3-yl)phenyl)-2H-indazole-7-carboxamide hydrochloride (MK4827, Merck & Co), MP124 (Mitsubishi Tanabe Pharma Co), ONO2231 (Ono Pharmaceutical Co Ltd), LT673 (LEAD Therapeutics), indole derivatives (PF1367338, Pfizer), 2-quinolinone and 2-quinoxalinone (U.S. Pat. No. 7,879,857), 2-alkylquinazolinone derivatives (U.S. Pat. No. 7,875,621), 2-pyridone derivatives (U.S. Pat. No. 7,863,280), pyrrolo[1,2-a]pyrazin-1(2H)-one and pyrrolo[1,2-d][1,2.4]triazin-1(2H)-one derivatives (U.S. Pat. No. 7,834,015), thieno[1,2-b]pyrazin-1(2H)-one derivatives (U.S. Pat. No. 7,834,015), and thieno[1,2-c]pyrazin-1(2H)-one derivatives (U.S. Pat. No. 7,834,015). These include, but are not limited to, isoquinoline (U.S. Pat. No. 7,825,129), phthalazinone derivatives (U.S. Pat. No. 7,092,193), indenoisoquinolinone (U.S. Pat. No. 7,652,028), 1H-benzimidazole-4-carboxamide (U.S. Pat. No. 7,595,406), 4-(substituted aryl)-5-hydroxyisoquinolinone derivatives (U.S. Pat. No. 7,425,563), and fused pyridazine derivatives (U.S. Pat. No. 7,402,580).

[0106] Radiation therapy can cause DNA damage and includes what are known as gamma rays, X-rays, electron beam radiation, and / or the delivery of radioisotopes directed at tumor cells. Other forms of DNA-damaging agents are also contemplated, such as microwave and UV radiation. All of these agents most likely cause widespread damage to DNA, DNA precursors, DNA replication and repair, and chromosome assembly and maintenance. X-ray dosages range from daily doses of 50-200 roentgens over prolonged periods (3-4 weeks) to single doses of 2000-6000 roentgens. Dosage ranges for radioisotopes vary widely and depend on the half-life of the isotope, the strength and type of radiation emitted, and uptake by neoplastic cells.

[0107] As used herein, the term "taxane" includes, but is not limited to, paclitaxel (Taxol, Abraxane®), docetaxel (Taxotere), and cabazitaxel (Jevtana), the approved dosage levels and routes of administration of which are set forth in the Physician's Desk Reference (Physicians' Desk Reference, 2017), the entire contents of which are incorporated herein by reference.

[0108] As used herein, the term "fatty acid binding protein" or "FABP" refers to fatty acid binding proteins (FABPs) that act as intracellular carriers that shuttle cannabinoids (and, by extension, fatty acid amides (FAAs)) to FAAH, where the cannabinoids are hydrolyzed and degraded. Additionally, cellular uptake of endocannabinoids (and, by extension, FAAs) and subsequent hydrolysis of endocannabinoids (and, by extension, FAAs) is enhanced by FABPs, and inhibiting the interaction of endocannabinoids (and, by extension, FAAs) with FABPs reduces uptake and hydrolysis of endocannabinoids (and, by extension, FAAs). FABPs include, for example, fatty acid binding protein 1 (FABP1), fatty acid binding protein 2 (FABP2), fatty acid binding protein 3 (FABP3), fatty acid binding protein 4 (FABP4), fatty acid binding protein 5 (FABP5), fatty acid binding protein 6 (FABP6), fatty acid binding protein 7 (FABP7), fatty acid binding protein 8 (FABP8), fatty acid binding protein 9 (FABP9), fatty acid binding protein 10 (FABP10), fatty acid binding protein 11 (FABP11), fatty acid binding protein 5-like (FABP5-like 1), fatty acid binding protein 5-like 2 (FABP5-like 2), fatty acid binding protein 5-like 3 (FABP5-like 3), fatty acid binding protein 5-like 4 (FABP5-like 4), fatty acid binding protein 5-like 5 (FABP5-like 5), fatty acid binding protein 5-like 6 (FABP5-like 6), and fatty acid binding protein 5-like 7 (FABP5-like 7) (Chmurzynska et al. 2006 and WO 2010 / 083532, the contents of each of which are incorporated herein by reference).

[0109] As used herein, the term "endocannabinoid" includes any molecule that activates a cannabinoid receptor. Examples of such receptors are CB1 and CB2. Examples of endocannabinoids are arachidonoylethanolamide (AEA) and 2-arachidonoylglycerol (2-AG).

[0110] As used herein, the term "FABP5 inhibitor" refers to any molecule that inhibits FABP5. Exemplary FABP5 inhibitors are disclosed in U.S. Patent Application Publication Nos. 14 / 413,621, 16 / 080,493, 2015 / 0183715, 2019 / 0062261, and U.S. Patent No. 9,604,904, all of which are incorporated herein by reference.

[0111] As used herein, the term "radiolabel" refers to a moiety containing a radioactive isotope of at least one element. Exemplary suitable radiolabels include, but are not limited to, carbon-11, nitrogen-13, oxygen-15, fluorine-18, gallium-68, zirconium-89, rubidium-82, copper-64, yttrium-86, bromine-76, iodine-123, iodine-124, technetium-99, xenon-133, and thallium-201. In some embodiments, the radiolabel is one used in positron emission tomography (PET). In some embodiments, the radiolabel is one used in single-photon emission computed tomography (SPECT).

[0112] The term "cancer" refers to a tumor resulting from abnormal or uncontrolled cell growth.

[0113] In certain embodiments, the subject compounds are useful in treating cancer.The term "cancer" as used herein includes breast, prostate, lung, colon, stomach, pancreas, ovary, brain and hematopoietic cancer, esophageal cancer, renal cell carcinoma, bladder cancer, head and neck cancer, leukemia, and sarcomas such as bile duct sarcoma and esophageal sarcoma.In particular, this includes breast and ovarian cancer, prostate cancer, pancreatic cancer, hepatocellular carcinoma, non-small cell lung cancer and small cell lung cancer (NSCLC and SCLC), colorectal cancer, leukemia, and lymphoma.For example, metastatic cancers such as metastatic prostate cancer are included.

[0114] As used herein, the term "therapeutic agent" refers to any agent used to treat a disease or that provides a beneficial therapeutic effect in a subject.

[0115] As used herein, the term "activity" refers to the activation, production, expression, synthesis, intercellular effect, and / or pathological or abnormal effect of a referenced molecule, either inside and / or outside a cell. Such molecules include, but are not limited to, cytokines, enzymes, growth factors, pro-growth factors, active growth factors, and pro-enzymes. Molecules such as cytokines, enzymes, growth factors, pro-growth factors, active growth factors, and pro-enzymes can be produced, expressed, or synthesized within the cell where they can exert their effect. Such molecules can also be transported outside the cell, to the extracellular matrix, where they can induce an effect on the extracellular matrix or adjacent cells. It is understood that activation of inactive cytokines, enzymes, and pro-enzymes can occur inside and / or outside the cell, and that both inactive and active forms can exist at any point inside and / or outside the cell. It is also understood that cells can have basal levels of such molecules for normal function, and that abnormally high or low levels of such active molecules can result in pathological or abnormal effects that can be corrected by pharmacological intervention.

[0116] In some embodiments, compounds of the present invention include all hydrates, solvates and complexes of compounds used in accordance with the present invention.

[0117] In some embodiments, when chiral or otherwise isomeric centers are present in compounds of the present invention, all forms of one or more such isomers, including enantiomers and diastereomers, are intended to be encompassed herein.

[0118] In some embodiments, when chiral or otherwise isomeric centers are present in the compounds of the present invention, only the enantiomeric forms are intended to be encompassed herein.

[0119] Compounds containing chiral centers can be used as racemic mixtures, enantiomerically enriched mixtures, or racemic mixtures can be separated using well-known techniques and the individual enantiomers used alone. The compounds described in this invention are in racemic form or as individual enantiomers.

[0120] As used herein, "enantiomers" are non-identical, non-superimposable mirror images of each other. For any given chiral compound, only one pair of enantiomers exists. Enantiomers can be separated using known techniques, including those described in Pure and Applied Chemistry 69, 1469-1474, (1997) IUPAC.

[0121] In cases in which compounds have unsaturated carbon-carbon double bonds, both the cis (Z) and trans (E) isomers are within the scope of this invention.

[0122] The compounds of the present invention may have naturally occurring tautomeric forms. Where the compounds can exist in tautomeric forms, such as keto-enol tautomers, each tautomeric form, whether existing in equilibrium or primarily in one form, is intended to be included within the scope of the present invention.

[0123] In the compound structures depicted herein, hydrogen atoms are not shown for carbon atoms with fewer than four bonds to non-hydrogen atoms, however, it is understood that there are sufficient hydrogen atoms present on said carbon atoms to satisfy the octet rule.

[0124] The present invention also provides isotopic variants of the compounds disclosed herein, wherein the isotopic atom is 2 H and / or isotope atoms 13 C. Thus, in the compounds provided herein, hydrogen may be enriched with deuterium isotopes. It is to be understood that the present invention encompasses all such isotopic forms.

[0125] It is understood that the structures described in the embodiments of the method above can be identical to the structures of the compounds described above.

[0126] Where numerical ranges are recited herein, it is understood that the invention contemplates every integer between the limits, inclusive, unless otherwise stated.

[0127] Unless otherwise specified, if the structure of a compound of the present invention includes an asymmetric carbon atom, it is understood that the compound exists as a racemate, a racemic mixture, and an isolated single enantiomer. All such isomeric forms of these compounds are expressly included in the present invention. Unless otherwise specified, each stereogenic carbon may have either an R or S configuration. Accordingly, unless otherwise specified, it is to be understood that isomers arising from such asymmetry (e.g., all enantiomers and diastereomers) are included within the scope of the present invention. Such isomers can be obtained in substantially pure form by classical separation techniques and by stereochemically controlled synthesis, such as that described in "Enantiomers, Racemates and Resolutions" by J. Jacques, A. Collet and S. Wilen, Pub. John Wiley & Sons, NY, 1981. For example, resolution can be carried out by preparative chromatography on a chiral column.

[0128] The present invention is also intended to include all isotopes of atoms present in the compounds disclosed herein. Isotopes include atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include C-13 and C-14.

[0129] Throughout this application, any designation of carbon in a structure, when used without further designation, refers to all isotopes of carbon, e.g. 12 C. 13 C or 14It will be noted that the term "C" is intended to represent C. Furthermore, 13 C or 14 Any of the compounds containing C can specifically have the structure of any of the compounds disclosed herein.

[0130] Throughout this application, any designation of hydrogen in a structure, when used without further designation, includes all isotopes of hydrogen, e.g. 1 H, 2 H or 3 It will also be noted that the term "H" is intended to represent H. 2 H or 3 Any of the H-containing compounds may specifically have the structure of any of the compounds disclosed herein.

[0131] Isotopically labeled compounds may generally be prepared by conventional techniques known to those skilled in the art, substituting an appropriate isotopically labeled reagent for the non-labeled reagent employed.

[0132] In the compounds used in the methods of the present invention, unless specifically defined otherwise, the substituents may be substituted or unsubstituted.

[0133] In the compounds used in the methods of the present invention, the alkyl, heteroalkyl, monocyclic, bicyclic, aryl, heteroaryl, and heterocyclic groups may be further substituted by replacing one or more hydrogen atoms with alternative non-hydrogen groups, including, but not limited to, halo, hydroxy, mercapto, amino, carboxy, cyano, carbamoyl, and aminocarbonyl and aminothiocarbonyl.

[0134] It is understood that the substituents and substitution patterns on the compounds used in the methods of the present invention can be selected by those skilled in the art to provide compounds that are chemically stable and can be easily synthesized from readily available starting materials by techniques known in the art. When a substituent is itself substituted with more than one group, it is understood that these multiple groups can be on the same carbon or on different carbons, so long as a stable structure is obtained.

[0135] In selecting compounds for use in the methods of the present invention, one of skill in the art will recognize that the various substituents, i.e., R1, R2, etc., should be selected according to well-known principles of chemical structure connectivity.

[0136] As used herein, "alkyl" includes both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, which may be unsubstituted or substituted. Thus, "C1-C n C1 to C alkyl n is defined to include individual groups each having 1, 2, ..., n-1, or n carbons in a linear or branched arrangement. For example, C1-C6, such as in "C1-C6 alkyl," is defined to include individual groups each having 1, 2, 3, 4, 5, or 6 carbons in a linear or branched arrangement, and specifically includes methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, pentyl, hexyl, and octyl.

[0137] As used herein, "alkenyl" refers to a straight-chain or branched non-aromatic hydrocarbon radical containing at least one carbon-carbon double bond, up to the maximum possible number of non-aromatic carbon-carbon double bonds, which may be unsubstituted or substituted. For example, "C2-C6 alkenyl" refers to an alkenyl radical having 2, 3, 4, 5, or 6 carbon atoms and up to 1, 2, 3, 4, or 5 carbon-carbon double bonds, respectively. Alkenyl groups include ethenyl, propenyl, butenyl, and cyclohexenyl.

[0138] The term "alkynyl" refers to a straight-chain or branched hydrocarbon radical containing at least one carbon-carbon triple bond, up to the maximum possible number of non-aromatic carbon-carbon triple bonds may be present, and may be unsubstituted or substituted. Thus, "C2-C6 alkynyl" refers to an alkynyl radical having 2 or 3 carbon atoms and 1 carbon-carbon triple bond, or 4 or 5 carbon atoms and up to 2 carbon-carbon triple bonds, or 6 carbon atoms and up to 3 carbon-carbon triple bonds. Alkynyl groups include ethynyl, propynyl, and butynyl.

[0139] "Alkylene," "alkenylene," and "alkynylene" are intended to mean divalent alkane, alkene, and alkyne radicals, respectively. It is understood that alkylene, alkenylene, and alkynylene can be linear or branched. Alkylene, alkenylene, and alkynylene can be unsubstituted or substituted.

[0140] As used herein, "heteroalkyl" includes both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms and at least one heteroatom in the chain or branch.

[0141] As used herein, "heterocycle" or "heterocyclyl," as used herein, is intended to mean a 5- to 10-membered non-aromatic ring containing 1-4 heteroatoms selected from the group consisting of O, N, and S, and includes bicyclic groups. Thus, "heterocyclyl" includes, but is not limited to, the following: imidazolyl, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, dihydropiperidinyl, tetrahydrothiophenyl, and the like. If the heterocycle contains nitrogen, it is understood that the corresponding N-oxides thereof are also encompassed by this definition.

[0142] As used herein, "cycloalkyl" is intended to mean a cyclic ring of an alkane having three to eight total carbon atoms, or any number within this range (i.e., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl).

[0143] As used herein, "monocyclic ring" includes any stable polyatomic carbon ring having up to 10 atoms, which may be unsubstituted or substituted. Examples of such non-aromatic monocyclic elements include, but are not limited to, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Examples of such aromatic monocyclic elements include, but are not limited to, phenyl.

[0144] As used herein, a "bicycle" includes any stable polyatomic carbon ring having up to 10 atoms fused to a polyatomic carbon ring having up to 10 atoms, each ring being independently unsubstituted or substituted. Examples of such non-aromatic bicyclic elements include, but are not limited to, decahydronaphthalene. Examples of such aromatic bicyclic elements include, but are not limited to, naphthalene.

[0145] As used herein, "aryl" is intended to mean any stable monocyclic, bicyclic, or polycyclic carbon ring having up to 10 atoms in each ring, wherein at least one ring is aromatic and can be unsubstituted or substituted. Examples of such aryl elements include, but are not limited to, phenyl, p-toluenyl (4-methylphenyl), naphthyl, tetrahydro-naphthyl, indanyl, biphenyl, phenanthryl, anthryl, or acenaphthyl. When the aryl substituent is bicyclic and one ring is non-aromatic, it is understood that attachment is via the aromatic ring.

[0146] As used herein, the term "polycyclic" refers to an unsaturated or partially unsaturated multiple fused ring structure, which may be unsubstituted or substituted.

[0147] The term "alkylaryl" refers to an alkyl group, as defined above, in which one or more bonds to hydrogen contained therein are replaced by a bond to an aryl group, as defined above. It is understood that the "arylalkyl" group is attached to a core molecule by a bond from the alkyl group, and that the aryl group serves as a substituent on the alkyl group. Examples of arylalkyl moieties include, but are not limited to, benzyl (phenylmethyl), p-trifluoromethylbenzyl (4-trifluoromethylphenylmethyl), 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 2-phenylpropyl, and the like.

[0148] The term "heteroaryl," as used herein, refers to a stable monocyclic, bicyclic, or polycyclic ring having up to 10 atoms in the ring, wherein at least one ring is aromatic and contains 1 to 4 heteroatoms selected from the group consisting of O, N, and S. Bicyclic aromatic heteroaryl groups include a phenyl, pyridine, pyrimidine, or pyrizidine ring (a) fused to a 6-membered aromatic (unsaturated) heterocyclic ring having one nitrogen atom; (b) fused to a 5- or 6-membered aromatic (unsaturated) heterocyclic ring having two nitrogen atoms; (c) fused to a 5-membered aromatic (unsaturated) heterocyclic ring having one nitrogen atom together with either one oxygen or one sulfur atom; or (d) fused to a 5-membered aromatic (unsaturated) heterocyclic ring having one heteroatom selected from O, N, or S.Heteroaryl groups within this definition include benzimidazolyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthopyridinyl, oxadiazolyl, oxazolyl, oxazoline, and isoxazoline. , oxetanyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, tetrazolyl, tetrazolopyridyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, azetidinyl, aziridinyl, 1,4-dioxanyl, hexahydroazepinyl, dihydrobenzimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydro Furanyl, dihydroimidazolyl, dihydroindolyl, dihydroisoxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, methylenedioxybenzoyl, tetrahydrofuranyl Examples of heteroaryl include, but are not limited to, tetrahydrothienyl, acridinyl, carbazolyl, cinnolinyl, quinoxalinyl, pyrazolyl, indolyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, isoxazolyl, isothiazolyl, furanyl, thienyl, benzothienyl, benzofuranyl, quinolinyl, isoquinolinyl, oxazolyl, isoxazolyl, indolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, and tetra-hydroquinoline. When a heteroaryl substituent is bicyclic and one ring is non-aromatic or does not contain a heteroatom, it is understood that attachment is via the aromatic ring or the heteroatom-containing ring, respectively.If the heteroaryl contains a nitrogen atom, it is understood that the corresponding N-oxides thereof are also encompassed by this definition.

[0149] The term "alkylheteroaryl" refers to an alkyl group, as defined above, in which one or more bonds to hydrogen contained therein are replaced by a bond to a heteroaryl group, as defined above. It is understood that the "alkylheteroaryl" group is attached to a core molecule by a bond from the alkyl group, and that the heteroaryl group acts as a substituent on the alkyl group. Examples of alkylheteroaryl moieties include, but are not limited to, -CH2-(CH4N), -CH2-CH2-(CH4N), and the like.

[0150] The terms "heterocycle" or "heterocyclyl" refer to a monocyclic or polycyclic ring system that may be saturated or contain one or more degrees of unsaturation and contains one or more heteroatoms. Preferred heteroatoms include N, O, and / or S, including N-oxides, sulfur oxides, and dioxides. Preferably, the ring is 3-10 membered and either saturated or has one or more degrees of unsaturation. Heterocycles can be unsubstituted or substituted, with multiple degrees of substitution permitted. Such rings can optionally be fused to one or more of another "heterocyclic" ring, heteroaryl ring, aryl ring, or cycloalkyl ring. Examples of heterocycles include, but are not limited to, tetrahydrofuran, pyran, 1,4-dioxane, 1,3-dioxane, piperidine, piperazine, pyrrolidine, morpholine, thiomorpholine, tetrahydrothiopyran, tetrahydrothiophene, 1,3-oxathiolane, and the like.

[0151] Alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl substituents may be substituted or unsubstituted unless otherwise specifically defined. In the compounds of the present invention, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, and heteroaryl groups may be further substituted by replacing one or more hydrogen atoms with alternative non-hydrogen groups. These include, but are not limited to, halo, hydroxy, mercapto, amino, carboxy, cyano, and carbamoyl.

[0152] As used herein, the term "halogen" refers to F, Cl, Br and I.

[0153] The terms "substituted," "substituted," and "substituent" refer to functional groups, as defined above, in which one or more bonds to a hydrogen atom contained therein have been replaced by a bond to a non-hydrogen or non-carbon atom, provided that normal valences are maintained and the substitution results in a stable compound. Substituent also includes groups in which one or more bonds to a carbon or hydrogen atom have been replaced by one or more bonds (including double or triple bonds) to a heteroatom. Examples of substituents include the above functional groups and halogens (i.e., F, Cl, Br, and I); alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, and trifluoromethyl; hydroxyl; alkoxy groups such as methoxy, ethoxy, n-propoxy, and isopropoxy; aryloxy groups such as phenoxy; arylalkyloxy groups such as benzyloxy (phenylmethoxy) and p-trifluoromethylbenzyloxy (4-trifluoromethylphenylmethoxy); heteroaryloxy groups; sulfonyl groups such as trifluoromethanesulfonyl, methanesulfonyl, and p-toluenesulfonyl; nitro, nitrosyl; mercapto; sulfanyl groups such as methylsulfanyl, ethylsulfanyl, and propylsulfanyl; cyano; amino groups such as amino, methylamino, dimethylamino, ethylamino, and diethylamino; and carboxyl. When multiple substituent moieties are disclosed or claimed, the substituted compound can be independently substituted singly or multiply by one or more of the disclosed or claimed substituent moieties. By independently substituted, it is meant that the (two or more) substituents can be the same or different.

[0154] It is understood that the substituents and substitution patterns in the compounds of the present invention can be selected by one skilled in the art to provide compounds that are chemically stable and can be readily synthesized from readily available starting materials by techniques known in the art and the methods described below. When a substituent is itself substituted with more than one group, it is understood that these multiple groups can be on the same carbon or on different carbons, so long as a stable structure results.

[0155] In selecting compounds of the present invention, one skilled in the art will recognize that the various substituents, i.e., R, R, etc., should be selected according to well-known principles of chemical structure connectivity. The various R groups attached to the aromatic rings of the compounds disclosed herein can be added to the rings by standard procedures, such as those described in Advanced Organic Chemistry: Part B: Reaction and Synthesis, Francis Carey and Richard Sundberg, (Springer) 5th ed. Edition. (2007), the contents of which are incorporated herein by reference.

[0156] The compounds used in the methods of the present invention may be prepared by techniques that are well known in organic synthesis and familiar to those skilled in the art, however, these may not be the only means to synthesize or obtain the desired compounds.

[0157] The compounds used in the methods of the present invention can be prepared by the techniques described in Vogel's Textbook of Practical Organic Chemistry, AI Vogel, AR Tatchell, BS Furnis, AJ Hannaford, PWG Smith, (Prentice Hall) 5th Edition (1996), March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Michael B. Smith, Jerry March, (Wiley-Interscience) 5th Edition (2007) and references therein (incorporated herein by reference). However, these may not be the only means for synthesizing or obtaining the desired compounds.

[0158] Another aspect of the present invention includes compounds used in the methods of the present invention as pharmaceutical compositions.

[0159] In some embodiments, the pharmaceutical composition comprises a compound of the invention and a pharmaceutically acceptable carrier.

[0160] As used herein, the term "pharmaceutically active agent" means any substance or compound suitable for administration to a subject, which provides biological activity or other direct effect in the treatment, cure, mitigation, diagnosis, or prevention of disease, or which affects the structure or any function of a subject. Pharmaceutically active agents include those listed in the Physicians' Desk Reference (PDR Network, LLC; 64th edition; November 15, 2009) and "Approved Drug Products with Therapeutic Equivalence Evaluations" (US Department of Health and Human Services, 30 th Pharmaceutically active agents having pendant carboxylic acid groups can be modified in accordance with the present invention using standard esterification reactions and methods that are readily available and known to those skilled in the art of chemical synthesis. If the pharmaceutically active agent does not have a carboxylic acid group, one skilled in the art would be able to design and introduce a carboxylic acid group into the pharmaceutically active agent, which can then be esterified, so long as the modification does not interfere with the biological activity or efficacy of the pharmaceutically active agent.

[0161] The compounds used in the methods of the present invention may be in the form of a salt. As used herein, a "salt" refers to a salt of a compound of the present invention modified by making an acid or base salt of the compound. In the case of a compound used to treat an infection or disease caused by a pathogen, the salt is pharmaceutically acceptable. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; and alkali or organic salts of acidic residues such as phenols. Salts can be made with organic or inorganic acids. Such acid salts include chloride, bromide, sulfate, nitrate, phosphate, sulfonate, formate, tartrate, maleate, malate, citrate, benzoate, salicylate, ascorbate, and the like. Phenolate salts are alkaline earth metal salts, sodium salts, potassium salts, or lithium salts. In this regard, the term "pharmaceutically acceptable salt" refers to relatively non-toxic inorganic and organic acid or base addition salts of the compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds of this invention, or by separately reacting the purified compounds of this invention in their free base or free acid form with a suitable organic or inorganic acid or base and isolating the salt thus formed. Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, and laurylsulfonate salts, and the like (see, e.g., Berge et al. (1977) "Pharmaceutical Salts," J. Pharm. Sci. 66:1-19).

[0162] The compounds of the present invention can also form salts with basic amino acids such as lysine and arginine, basic sugars such as N-methylglucamine and 2-amino-2-deoxyglucose, and any other physiologically non-toxic basic substances.

[0163] The compounds used in the methods of the present invention can be administered in various forms, including those detailed herein. Treatment with the compounds can be a component of combination therapy or adjunctive therapy, i.e., a subject or patient in need of a drug is treated or administered with one or more compounds of the present invention together with another drug for the disease. This combination therapy can be sequential therapy, where the patient is first treated with one drug and then with another agent, or the two drugs are administered simultaneously. They can be administered independently by the same administration route or two or more different administration routes, depending on the dosage form used.

[0164] As used herein, a "pharmaceutically acceptable carrier" is a pharmaceutically acceptable solvent, suspending agent, or vehicle for delivering a compound of the present invention to an animal or human. The carrier may be liquid or solid and is selected taking into consideration the intended method of administration. Liposomes are also pharmaceutically acceptable carriers, as are sustained release vehicles.

[0165] The dosage of the compound administered in a treatment will vary depending on factors such as the pharmaceutical characteristics of the particular chemotherapeutic agent and its mode and route of administration; the age, sex, metabolic rate, absorption efficiency, health, and weight of the recipient; the nature and extent of the condition; the type of concurrent treatment being administered; the frequency of treatment; and the desired therapeutic effect.

[0166] Dosage units of the compounds used in the methods of the present invention may contain a single compound or a mixture thereof with an additional anti-tumor agent. The compounds can be administered in oral dosage forms as tablets, capsules, pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. The compounds can also be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramuscular form, or can be introduced directly into or locally onto the site of a disease or lesion, for example, by injection, topical administration, or other methods, all using dosage forms well known to those skilled in the pharmaceutical arts.

[0167] The compounds used in the methods of the present invention can be administered in a mixture with a suitable pharmaceutical diluent, filler, excipient, or in a carrier such as novel programmable sustained-release multicompartment nanospheres (collectively referred to herein as a pharmaceutically acceptable carrier), appropriately selected for the intended administration form and consistent with conventional pharmaceutical practice. The units can be in a form suitable for oral, nasal, rectal, topical, intravenous or direct injection, or parenteral administration. The compounds can be administered alone or in a mixture with a pharmaceutically acceptable carrier. The carrier can be solid or liquid, and the type of carrier is generally selected based on the type of administration to be used. The active agent can be co-administered in the form of a tablet or capsule, liposomes, as an agglomerated powder, or in liquid form. Examples of suitable solid carriers include lactose, sucrose, gelatin, and agar. Capsules or tablets can be easily formulated and can be easily swallowed or chewed; other solid forms include granules and bulk powders. Tablets may contain suitable binders, lubricants, diluents, disintegrants, colorants, flavoring agents, flow inducers, and melting agents. Examples of suitable liquid dosage forms include aqueous solutions or suspensions, pharmaceutically acceptable fats and oils, other organic solvents including alcohols or esters, emulsions, syrups or elixirs, suspensions, solutions and / or suspensions reconstituted from non-effervescent granules, and effervescent preparations reconstituted from effervescent granules. Such liquid dosage forms may contain, for example, suitable solvents, preservatives, emulsifiers, suspending agents, diluents, sweeteners, thickeners, and melting agents. Oral dosage forms optionally contain flavorings and coloring agents. Parenteral and intravenous forms may also contain minerals and other materials to make them compatible with the type of injection or delivery system selected.

[0168] Techniques and compositions for preparing dosage forms useful in the present invention are described in the following references: 7 Modern Pharmaceutics, Chapters 9 and 10 (Banker & Rhodes, Editors, 1979); Pharmaceutical Dosage Forms: Tablets (Lieberman et al., 1981); Ansel, Introduction to Pharmaceutical Dosage Forms 2nd Edition (1976); Remington's Pharmaceutical Sciences, 17th ed. (Mack Publishing Company, Easton, Pa., 1985); Advances in Pharmaceutical Sciences (David Ganderton, Trevor Jones, Eds., 1992); Advances in Pharmaceutical Sciences Vol. 7 (David Ganderton, Trevor Jones, James McGinity, Eds., 1995); Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms (Drugs and the Pharmaceutical Sciences, Series 36 (James McGinity, Ed., 1989);Pharmaceutical Particulate Carriers: Therapeutic Applications: Drugs and the Pharmaceutical Sciences, Vol 61 (Alain Rolland, Ed., 1993);Drug Delivery to the Gastrointestinal Tract (Ellis Horwood Books in the Biological Sciences. Series in Pharmaceutical Technology; JG Hardy, SS Davis, Clive G. Wilson, Eds.); Modern Pharmaceutics Drugs and the Pharmaceutical Sciences, Vol. 40 (Gilbert S. Banker, Christopher T. Rhodes, Eds.). All of the above publications are incorporated herein by reference.

[0169] Tablets may contain suitable binders, lubricants, disintegrants, colorants, flavoring agents, flow-inducing agents, and melting agents. For example, for oral administration in unit dosage form, such as a tablet or capsule, the active drug ingredient can be combined with an oral, non-toxic, pharmaceutically acceptable inert carrier such as lactose, gelatin, agar, starch, sucrose, glucose, methylcellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol, etc. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, etc. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, etc. Disintegrants include, but are not limited to, starch, methylcellulose, agar, bentonite, xanthan gum, etc.

[0170] The compounds used in the methods of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from various phospholipids, such as lecithin, sphingomyelin, proteolipids, protein-encapsulating vesicles, or from cholesterol, stearylamine, or phosphatidylcholine. The compounds can be administered as a component of a tissue-targeting emulsion.

[0171] The compounds used in the methods of the present invention can also be coupled to soluble polymers as targetable drug carriers or prodrugs. Such polymers include polyvinylpyrrolidone, pyran copolymers, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues. Furthermore, the compounds can be coupled to a variety of biodegradable polymers useful for achieving controlled drug release, such as polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, and crosslinked or amphiphilic block copolymers of hydrogels.

[0172] Gelatin capsules may contain the active ingredient compound and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, etc. Similar diluents can be used to prepare compressed tablets. Both tablets and capsules can be prepared as immediate release products or as sustained release products to provide continuous release of drug over several hours. Compressed tablets can be sugar-coated or film-coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric-coated for selective disintegration in the gastrointestinal tract.

[0173] For oral administration in liquid dosage form, the oral drug ingredients are combined with any oral, non-toxic, pharmaceutically acceptable inert carrier, such as ethanol, glycerol, water, etc. Examples of suitable liquid dosage forms include aqueous solutions or suspensions, pharmaceutically acceptable fats and oils, other organic solvents including alcohols or esters, emulsions, syrups or elixirs, suspensions, solutions and / or suspensions reconstituted from non-effervescent granules, and effervescent preparations reconstituted from effervescent granules. Such liquid dosage forms may contain, for example, suitable solvents, preservatives, emulsifiers, suspending agents, diluents, sweeteners, thickeners, and melting agents.

[0174] Liquid dosage forms for oral administration can contain coloring and flavoring agents to increase patient acceptance. In general, water, a suitable oil, saline, aqueous dextrose (glucose) and related sugar solutions, and glycols, such as propylene glycol or polyethylene glycol, are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain a water-soluble salt of the active ingredient, suitable stabilizers, and, if necessary, buffer substances. Antioxidants such as sodium bisulfite, sodium sulfite, or ascorbic acid, alone or in combination, are suitable stabilizers. Citric acid and its salts and sodium EDTA are also used. In addition, parenteral solutions can contain preservatives such as benzalkonium chloride, methyl or propyl paraben, and chlorobutanol. Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Company, a standard reference text in this field.

[0175] The compounds used in the methods of the present invention can also be administered in intranasal form using suitable intranasal vehicles, or via transdermal routes, using transdermal skin patch formulations well known to those skilled in the art. To be administered in the form of a transdermal delivery system, the dosage administration will generally be continuous rather than intermittent throughout the dosage regimen.

[0176] Parenteral and intravenous forms may also include minerals and other materials, such as solutol and / or ethanol, to make them compatible with the type of injection or delivery system chosen.

[0177] The compounds and compositions of the present invention can be administered in oral dosage forms such as tablets, capsules, pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. The compounds can also be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramuscular form, or can be introduced directly into the affected area, such as a wound, including a skin ulcer, for example, by topical administration, injection, or other methods, all using dosage forms well known to those skilled in the pharmaceutical arts.

[0178] Specific examples of pharmaceutically acceptable carriers and excipients that can be used to formulate oral dosage forms of the present invention are described in U.S. Pat. No. 3,903,297 (Robert), issued Sep. 2, 1975. Techniques and compositions for preparing dosage forms useful in the present invention are described in the following references: 7 Modern Pharmaceutics, Chapters 9 and 10 (Banker & Rhodes, Editors, 1979); Pharmaceutical Dosage Forms: Tablets (Lieberman et al., 1981); Ansel, Introduction to Pharmaceutical Dosage Forms 2nd Edition (1976); Remington's Pharmaceutical Sciences, 17th ed. (Mack Publishing Company, Easton, Pa., 1985); Advances in Pharmaceutical Sciences (David Ganderton, Trevor Jones, Eds., 1992); Advances in Pharmaceutical Sciences Vol 7. (David Ganderton, Trevor Jones, James McGinity, Eds., 1995); Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms (Drugs and the Pharmaceutical Sciences, Series 36 (James McGinity, Ed., 1989);Pharmaceutical Particulate Carriers: Therapeutic Applications: Drugs and the Pharmaceutical Sciences, Vol 61 (Alain Rolland, Ed., 1993);Drug Delivery to the Gastrointestinal Tract (Ellis Horwood Books in the Biological Sciences.Series in Pharmaceutical Technology; JG Hardy, SS Davis, Clive G. Wilson, Eds.); Modern Pharmaceutics Drugs and the Pharmaceutical Sciences, Vol. 40 (Gilbert S. Banker, Christopher T. Rhodes, Eds.). All of the above publications are incorporated herein by reference.

[0179] The term "prodrug," as used herein, refers to any compound that, when administered to a biological system, produces a compound of the invention as a result of a spontaneous chemical reaction, an enzyme-catalyzed chemical reaction, photolysis, and / or a metabolic chemical reaction. Thus, prodrugs are covalently modified analogs or latent forms of the compounds of the invention.

[0180] The active ingredient can be administered orally in solid dosage forms such as capsules, tablets, powders, and chewing gum; or in liquid dosage forms such as elixirs, syrups, and suspensions, including, but not limited to, mouthwashes and toothpastes. It can also be administered parenterally in sterile liquid dosage forms.

[0181] Solid dosage forms such as capsules and tablets can be enterically coated to prevent the release of the active ingredient compound before they reach the small intestine. Materials that can be used as enteric coatings include, but are not limited to, sugars, fatty acids, proteinaceous substances such as gelatin, waxes, shellac, cellulose acetate phthalate (CAP), methyl acrylate-methacrylic acid copolymer, cellulose acetate succinate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate (hypromellose acetate succinate), polyvinyl acetate phthalate (PVAP), and methyl methacrylate-methacrylic acid copolymer.

[0182] The compounds and compositions of the present invention may be coated onto stents for temporary or permanent implantation into the cardiovascular system of a subject.

[0183] Each embodiment disclosed herein is contemplated as being applicable to each of the other embodiments disclosed, and accordingly, all combinations of the various elements described herein are within the scope of the invention.

[0184] The present invention will be better understood by reference to the experimental details that follow, but those skilled in the art will readily recognize that the specific experiments detailed are merely illustrative of the invention, as more fully described in the claims that follow. [Example]

[0185] Example 1. Synergistic anti-cancer activity in vitro of a combination of a taxane and a FABP5 inhibitor Materials and Methods cell line PC3 cells were obtained from the American Type Culture Collection (ATCC; CRL-1435; Manassas, VA) and confirmed by the ATCC Human Short Tandem Repeat Profiling Cell Authentication Service. DU-145 and 22Rv1 cells were also obtained from ATCC (HTB-81 and CRL-2505, respectively). PC3, DU-145, and 22Rv1 cell lines were each grown in Roswell Park Memorial Institute 1640 (RPMI 1640) (Gibco-Thermo Fisher Scientific, Gaithersburg, MD) supplemented with 10% fetal bovine serum (FBS) (Gemini Bio-Products, West Sacramento, CA) and 100 units / mL penicillin / streptomycin (Gibco-Thermo Fisher Scientific) in a humidified incubator containing 95% air and 5% CO2. WI-38 cells were obtained from ATCC (CCL-75). WI-38 cells were grown in Dulbecco's modified Eagle's medium (DMEM) (Gibco-Thermo Fisher Scientific) supplemented with 10% FBS and 100 units / mL penicillin / streptomycin in a humidified incubator containing 95% air and 5% CO2. RWPE-1 cells were purchased from ATCC (CRL-11609). RWPE-1 cells were grown in keratinocyte serum-free medium (K-SFM) (Gibco-Thermo Fisher Scientific) supplemented with 25 mg of bovine pituitary extract (BPE), 1 mg of recombinant human epidermal growth factor (EGF), and 100 units / mL penicillin / streptomycin in a humidified incubator containing 95% air and 5% CO2.

[0186] drugs SBFI-102 and SBFI-103 were synthesized as described (Yan, S. et al. 2018). Docetaxel was obtained from Sigma-Aldrich (St. Louis, MO). Cabazitaxel was a gift from Discovery Chemistry Laboratory (Institute of Chemical Biology and Drug Discovery, Stony Brook University, Stony Brook, NY).

[0187] Cytotoxicity assay The cytotoxicity of SBFI-102, SBFI-103, docetaxel, and cabazitaxel (individually and in combination) was determined using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) colorimetric assay (Sigma-Aldrich). PC3 (2500 cells / well), DU-145, 22Rv1, WI-38 (5000 cells / well), and RWPE-1 (10,000 cells / well) cells were seeded in 96-well plates and incubated at 37°C for 24 hours in their respective media (RPMI 1640 for PC3 / DU-145 / 22Rv1 cells, DMEM for WI-38 cells, and K-SFM for RWPE-1 cells). PC3, DU-145, and 22Rv1 cells were treated with RPMI 1640 supplemented with 1% FBS containing 0.1 μM to 100 μM SBFI-102 or SBFI-103 and / or 0.003 nM to 300 nM docetaxel or cabazitaxel (either individually or in combination with SBFI-102 or SBFI-103). WI-38 cells were treated with DMEM supplemented with 1% FBS containing 0.1 μM to 100 μM SBFI-102 or SBFI-103. RWPE-1 cells were treated with K-SFM supplemented with 25 mg BPE and 1 mg recombinant human EGF containing 0.1 μM to 100 μM SBFI-102 or SBFI-103. All drugs for in vitro experiments were dissolved in DMSO at a final concentration of 0.1%. Additionally, treatment medium appropriate for each cell line, supplemented with 0.1% DMSO or 1% sodium dodecyl sulfate, was used as either a positive or negative control, respectively. After a 72-hour incubation period, cells were washed with PBS and treated with MTT (0.5 mg / mL in serum-free RPMI 1640, serum-free DMEM, or K-SFM) for 4 hours. Cells were then solubilized using DMSO, and absorbance was read at 562 nm on an F5 Filtermax Multi-Mode Microplate Reader (Molecular Devices, Sunnyvale, CA).

[0188] Analysis of drug combination effects Using ComboSyn software, the synergy between docetaxel / cabazitaxel and SBFI-102 or SBFI-103 was determined by the combination index (CI) method, which uses the median-effective principle of the law of mass action derived from Chou and Talalay (Chou, TC 2006). Briefly, the individual drug concentrations that resulted in the desired percentage of cells affected (Fa) were determined (i.e., the concentrations of SBFI-102, SBFI-103, docetaxel, or cabazitaxel that resulted in the same percentage of cells being killed). The concentrations that resulted in the desired Fa for each drug (e.g., Fa = 0.5 represents 50% of cells affected) were plotted on the XY axis, and a straight line was drawn to connect the data points. Coadministration of two drugs that achieved the same desired Fa was then plotted on the same axis. Data points above the line (CI>1) represent antagonism, data points on the line (CI=1) represent additive interactions, and data points below the line (CI<1) represent synergy.

[0189] [Table 1]

[0190] [Table 2]

[0191] The cytotoxic effects of SBFI-102 (Figure 2A) and SBFI-103 (Figure 2B) were evaluated in human-derived PC3, DU-145, and 22Rv1 cells expressing FABP5 (Kawaguchi, K. et al. 2016). SBFI-102 and SBFI-103 produced dose-dependent cytotoxicity in each cell line tested: PC3 cells had IC50 values ​​of 11.4 and 6.3 μM, respectively; DU-145 cells had IC50 values ​​of 8.9 and 3.3 μM, respectively; and 22Rv1 cells had IC50 values ​​of 10.1 and 3.1 μM, respectively. Both SBFI-102 and SBFI-103 showed less cytotoxicity in RWPE-1 cells (a normal prostate cell line), producing IC50 values ​​of 26.0 and 20.6 μM, respectively (Figure 2A, B). Both SBFI-102 and SBFI-103 exhibited less cytotoxicity in WI-38 cells (a normal lung cell line), yielding IC50 values ​​of 29.4 and 29.6 μM, respectively (Figure 2A, B).

[0192] Docetaxel produced dose-dependent cytotoxicity in each cell line tested: PC3 cells had an IC50 value of 1.9 nM (Figure 3A); DU-145 cells had an IC50 value of 0.8 nM (Figure 3B); and 22Rv1 cells had an IC50 value of 0.3 nM (Figure 3C). Similarly, cabazitaxel produced dose-dependent cytotoxicity in each cell line tested: PC3 cells had an IC50 value of 1.6 nM (Figure 4A); DU-145 cells had an IC50 value of 0.2 nM (Figure 4B); and 22Rv1 cells had an IC50 value of 0.3 nM (Figure 4C).

[0193] The combination of docetaxel with the FABP5 inhibitors SBFI-102 or SBFI-103 resulted in greater cytotoxicity in PC3, DU-145, and 22Rv1 cells than either drug when administered independently (Figure 5). A synergistic relationship between docetaxel and the FABP5 inhibitors was observed in each cell line (CI < 1) (Table 1).

[0194] The combination of cabazitaxel with the FABP5 inhibitors SBFI-102 or SBFI-103 resulted in greater cytotoxicity in PC3, DU-145, and 22Rv1 cells than either drug when administered independently (Figure 6). A synergistic relationship between cabazitaxel and the FABP5 inhibitors was also observed (Table 2).

[0195] Example 2. Synergistic anti-cancer activity in vivo by the combination of a taxane and a FABP5 inhibitor Materials and Methods animal Male BALB / c nude mice (BALB / cOlaHsd-Foxn1nu, 20-30 g, 7-8 weeks old) (Envigo RMS Inc, Indianapolis, IN) were used for all experiments. Animals were individually housed at room temperature, maintained on a 12:12 h light:dark cycle, and had free access to food and water. Euthanasia was performed using CO2 asphyxiation. All experiments were approved by the Stony Brook University Animal Care and Use Committee.

[0196] Subcutaneous tumor implantation Male BALB / c nude mice were subcutaneously inoculated with PC3 cells. Briefly, cells (1 × 10 6 Tumors (1000 / mouse) were resuspended in 100 μL of a 1:1 mixture of phosphate-buffered saline (PBS):Matrigel (Corning Inc, Corning, NY) and implanted into one dorsal flank using a 21G needle. Tumor length (L) and tumor width (W) were measured twice weekly using digital calipers, and tumor volume (V) was calculated as (V = [L × W] / 2). When tumor volume reached approximately 150–200 mm3, animals were grouped and drug administration began. Humane endpoints for all animals were as follows: animals bearing tumor burden for more than 35 days, loss of more than 15% body weight (recorded twice weekly), tumor ulceration, paralysis, inability to groom, bleeding, respiratory distress, and / or tumor volume reaching 1500 mm3.

[0197] Drug administration SBFI-102, SBFI-103, and docetaxel were each reconstituted in a 1:1:8 mixture of dimethyl sulfoxide (DMSO) (Thermo Fisher Scientific, Hampton, NH):Cremaphor-EL (Sigma-Aldrich):saline. 20 mg / kg of SBFI-102 and SBFI-103 were administered daily via intraperitoneal injection (ip) using a 27G needle. 5 or 10 mg / kg of docetaxel was administered ip once weekly. All drugs were administered in a volume of 10 μL / g of body weight.

[0198] Quantification and Statistical Analysis All data were obtained from at least three independent experiments, and the values ​​listed in each figure legend represent each independent experiment or animal. Data from all in vivo experiments were analyzed using one-way analysis of variance with Tukey's post-hoc test (GraphPad Prism, version 8.0.2). Data are expressed as mean ± SEM, and P < 0.05 was considered statistically significant. The degree of significance is indicated in each figure legend.

[0199] Administration of SBFI-102 or SBFI-103 (20 mg / kg, i.p., once daily) significantly reduced tumor growth (Figure 7A). Similarly, administration of docetaxel (5 or 10 mg / kg, i.p., once weekly) reduced tumor growth, with the 5 mg / kg dose producing tumor growth inhibition similar to that observed with the FABP5 inhibitor, and the 10 mg / kg dose producing nearly complete growth inhibition (Figures 7A-D).

[0200] To determine whether SBFI-102 and SBFI-103 potentiate the tumor-suppressing effects of docetaxel, the FABP5 inhibitors were administered in combination with a submaximal dose of docetaxel (5 mg / kg). Consistent with the in vitro efficacy data, coadministration of docetaxel with SBFI-102 or SBFI-103 resulted in greater inhibition of tumor growth than treatment with each compound alone, an effect equivalent in magnitude to a 10 mg / kg docetaxel dose (Figure 8A-D).

[0201] Consideration Prostate cancer (PCa) remains the second leading cause of cancer-related death among men. Taxanes, such as docetaxel and cabazitaxel, are used as standard chemotherapeutic treatment regimens for treating untreated castration-resistant prostate cancer (Tannock, IF et al. 2004; Galletti, G. et al. 2017; Antonarakis, E. & Paller, ES 2011; de Bono, JS 2010; Higano, CS & Crawford, ED 2011). Despite the clinical availability of docetaxel, cabazitaxel, and newer generation taxane chemotherapeutic agents, prostate tumors often develop resistance to these agents (Galletti, G. et al. 2017; Hongo, H. et al. 2018).

[0202] Combination therapy consisting of docetaxel / cabazitaxel and other chemotherapy drugs may result in enhanced antitumor efficacy or allow the use of lower taxane doses in patients, thus reducing taxane resistance and potentially reducing adverse effects associated with taxane chemotherapy drugs (Antonarakis, E. & Paller, ES 2011; Cella, D. et al. 2003; Baker, J. et al. 2009; Sperlich, C. & Saad, F. 2013).

[0203] Fatty acid binding protein 5 (FABP5) is an intracellular lipid carrier whose expression is upregulated in metastatic PCa, enhancing cell growth, invasion, and tumorigenesis. FABP5 inhibitors based on the truxillate monoester scaffold have been developed, including the first-generation inhibitor Stony Brook Fatty Acid Binding Protein Inhibitor 26 (SBFI-26) (Berger, W. et al. 2012; Kaczocha, M. et al. 2014). FABP5 inhibitors that exhibit enhanced potency or selectivity for FABP5 have been identified (Yan, S. et al. 2018). SBFI-26 suppresses PCa cell growth, migration, invasion, tumorigenesis, and metastasis in vitro and in vivo (Al-Jameel, W. et al. 2017), suggesting that FABP5 inhibitors may constitute effective antitumor agents. Therefore, we evaluated whether FABP5 inhibitors synergize with clinically used taxanes to induce cytotoxicity in vitro and attenuate tumor growth in vivo.

[0204] The inventors have found that SBFI-102 and SBFI-103 produce cytotoxicity in PCa cells. Co-incubation of PCa cells with a FABP5 inhibitor and docetaxel or cabazitaxel produced synergistic cytotoxic effects in vitro. Treatment of mice with a FABP5 inhibitor reduced tumor growth, and the combination of a FABP5 inhibitor with a submaximal dose of docetaxel reduced tumor growth to a greater extent than treatment with either drug alone. Thus, FABP5 inhibitors enhance the cytotoxicity and tumor-suppressing effects of taxanes in PCa cells. The ability of these drugs to synergize may enable more effective antitumor activity, while allowing for lower doses of docetaxel or cabazitaxel, potentially reducing taxane resistance and taxane-associated toxicity.

[0205] References Adamson, J., Morgan, E.A., Beesley, C., et al. (2003) High‐level expression of cutaneous fatty acid‐binding protein in prostatic carcinomas and its effect on tumorigenicity. Oncogene 22, 2739‐2749. Ahmad, I., Mui, E., Galbraith, L., Patel, R., Tan, E.H., Salji, M., Rust, A.G., Repiscak, P., Hedley, A., Markert, E., Loveridge, C., van der Weyden, L., Edwards, J., Sansom, O.J., Adams, D.J., Leung, H.Y. (2016) Sleeping Beauty screen reveals Pparg activation in metastatic prostate cancer. Proc Natl Acad Sci U S A, 113, 8290-8295. Al‐Jameel, W., Gou, X., Forootan, S.S., et al. (2017) Inhibitor SBFI26 suppresses the malignant progression of castration‐resistant PC3‐M cells by competitively binding to oncogenic FABP5. Oncotarget 8, 31041‐31056. Antonarakis, E., Paller, E.S. (2011) Cabazitaxel: a novel second‐line treatment for metastatic castration‐resistant prostate cancer. Drug Des Devel Ther. 5, 117‐124. Baker, J., Ajani, J., Scotte, F., et al. (2009) Docetaxel‐related side effects and their management. Eur J Oncol Nurs. 13, 49‐59. Bao, Z., Malki, M.I., Forootan, S.S., Adamson, J., Forootan, F.S., Chen, D., Foster, C.S., Rudland, P.S., Ke, Y. (2013) A novel cutaneous Fatty Acid-binding protein-related signaling pathway leading to malignant progression in prostate cancer cells. Genes Cancer 4, 297-314. Berger, W.T., Ralph, B.P., Kaczocha, M., Sun, J., Balius, T.E., Rizzo, R.C., Haj-Dahmane, S., Ojima, I., and Deutsch, D.G. (2012) Targeting fatty acid binding protein (FABP) anandamide transporters - a novel strategy for development of anti-inflammatory and anti-nociceptive drugs. PLoS One 7, e50968. de Bono, J.S., Oudard, S., Ozguroglu, M., et al. (2010) Prednisone plus cabazitaxel or mitoxantrone for metastatic castration‐resistant prostate cancer progressing after docetaxel treatment: a randomized open‐label trial. The Lancet 376, 1147‐1154. Bray, F., Ferlay, J., Soerjomataram, I., Siegel, R.L., Torre, L.A., Jemal, A. (2018) Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 68, 394‐424. Brod et al. (2000) Annals of Neurology, 47:127-131. Cella, D., Peterman, A., Hudgens, S., Webster, K., Socinski, M.A. (2003) Measuring the side effects of taxane therapy in oncology: The Functional Assessment of Cancer Therapy‐taxane (FACT‐taxane). Cancer 98, 822‐831. Chou, T.C. (2006) Theoretical basis, experimental design, and computerized simulation of synergism and antagonism in drug combination studies. Pharmacol Rev. 58, 621‐681. Deep, G., Schlaepfer, I. (2016) Aberrant lipid metabolism promotes prostate cancer: role in cell survival under hypoxia and extracellular vesicles biogenesis. Int J Mol Sci. 17, 1061. Forootan, F.S., Forootan, S.S., Gou, X., et al. (2016) Fatty acid activated PPARgamma promotes tumorigenicity of prostate cancer cells by up regulating VEGF via PPAR responsive elements of the promoter. Oncotarget 7, 9322‐9339. Forootan, F.S., Forootan, S.S., Malki, M.I., Chen, D., Li, G., Lin, K., Rudland, P.S., Foster, C.S., Ke, Y. (2014) The expression of C-FABP and PPARγ and their prognostic significance in prostate cancer. Int J Oncol 44, 265-275. Frieling, J.S., Basanta, D., Lynch, C.C. (2015) Current and emerging therapies for bone metastatic castration‐resistant prostate cancer. Cancer Control 22, 109‐120. Fujita, K., Kume, H., Matsuzaki, K., Kawashima, A., Ujike, T., Nagahara, A., Uemura, M., Miyagawa, Y., Tomonaga, T., Nonomura, N. (2017) Proteomic analysis of urinary extracellular vesicles from high Gleason score prostate cancer. Sci rep. 7, 42961. Furuhashi, M. and Hotamisligil, G. S. (2008) Fatty acid-binding proteins: role in metabolic diseases and potential as drug targets. Nat Rev Drug Discov 7, 489-503. Galletti, G., Leach, B.I., Lam, L., Tagawa, S.T. (2017) Mechanisms of resistance to systemic therapy in metastatic castration‐resistant prostate cancer. Cancer Treat Rev. 57, 16‐27. Guidance for Industry. In vivo drug metabolism / drug interaction studies - study design, data analysis, and recommendations for dosing and labeling, U.S. Dept. Health and Human Svcs., FDA, Ctr. for Drug Eval. and Res., Ctr. For Biologics Eval. and Res., Clin. Pharm., Nov. 1999 <http: / / www.fda.gov / cber / gdlns / metabol.pdf>. Higano, C.S., Crawford, E.D. (2011) New and emerging agents for the treatment of castration‐resistant prostate cancer. Urol Oncol. 29, 1‐8. Hongo, H., Kosaka, T., Oya, M. (2018) Analysis of cabazitaxel‐resistant mechanism in human castration‐resistant prostate cancer. Cancer Sci. 109, 2937‐2945.Jing, C., Beesley, C., Foster, C.S., et al. (2000) Identification of the messenger RNA for human cutaneous fatty acid‐binding protein as a metastasis inducer. Cancer Res. 60, 2390‐2398. Kaczocha, M., Rebecchi, M.J., Ralph, B.P., et al. (2014) Inhibition of fatty acid binding proteins elevates brain anandamide levels and produces analgesia. PLoS One 9, e94200. Kawaguchi, K., Kinameri, A., Suzuki, S., Senga, S., Ke, Y., Fujii, H. (2016) The cancer-promoting gene fatty acid‐binding protein 5 (FABP5) is epigenetically regulated during human prostate carcinogenesis. Biochem J. 473, 449‐461. Kleinschmidt-DeMasters et al. (2005) New England Journal of Medicine, 353:369-379. Langer-Gould et al. (2005) New England Journal of Medicine, 353:369-379. Morgan, E.A., Forootan, S.S., Adamson, J., et al. (2008) Expression of cutaneous fatty acid‐binding protein (C‐FABP) in prostate cancer: potential prognostic marker and target for tumourigenicity‐suppression. Int J Oncol. 32, 767‐775.Rudick et al. (2006) New England Journal of Medicine, 354:911-923. Sperlich, C., Saad, F. (2013) Optimal management of patients receiving cabazitaxel‐based chemotherapy. Can Urol Assoc J. 7, S18‐S24. Tannock, I.F., de Wit, R., Berry, W.R., et al. (2004) Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med. 351, 1502‐1512. Vollmer et al. (2008) “Glatiramer acetate after induction therapy with mitoxantrone in relapsing multiple sclerosis” Multiple Sclerosis, 00:1-8. Yan, S., Elmes, M.W., Tong, S., et al. (2018) SAR studies on truxillic acid mono esters as a new class of antinociceptive agents targeting fatty acid binding proteins. Eur J Med Chem. 154, 233‐252. Zadra, G., Photopoulos, C., Loda, M. (2013) The fat side of prostate cancer. Biochim Biophys Acta. 1831, 1518‐1532. The invention as originally claimed is as follows: [1] A method for treating cancer in a subject, comprising administering to the subject an effective amount of a FABP5 inhibitor in conjunction with an anti-cancer therapy. [2] The method of [1], comprising periodically administering to the subject a certain amount of the FABP5 inhibitor and the anti-cancer therapy, wherein the amount, when taken together, is effective to treat the subject. [3] The method of [1] or [2], wherein the amount of the FABP5 inhibitor and the amount of the anticancer therapy, when administered together, are more effective for treating the subject than when the same amount of each agent is administered alone. [4] The method according to any one of [1] to [3], wherein the subject is receiving the anticancer therapy before initiation of FABP5 inhibitor therapy. [5] The method according to any one of [1] to [4], wherein the subject is receiving the FABP5 inhibitor therapy before the initiation of the anticancer therapy. [6] The method according to any one of [1] to [5], wherein the FABP5 inhibitor and the anticancer therapy are administered sequentially. [7] The method according to any one of [1] to [6], wherein the FABP5 inhibitor is administered first, and then the anticancer therapy is administered. [8] The method according to any one of [1] to [6], wherein the anticancer therapy is administered first, and then the FABP5 inhibitor is administered. [9] The method according to any one of [1] to [5], wherein the FABP5 inhibitor and the anticancer therapy are administered simultaneously.

[10] The method according to any one of [1] to [9], wherein the FABP5 inhibitor is administered orally, intravenously, or intraperitoneally.

[11] The method of [1], wherein the anticancer therapy is a taxane.

[12] The method according to

[11] , wherein the taxane is administered intravenously or intraperitoneally.

[13] The method according to any one of [1] to

[12] , wherein the cancer expresses FABP5.

[14] The method according to any one of [1] to

[13] , wherein the cancer overexpresses FABP5.

[15] The method according to any one of [1] to

[14] , wherein the cancer is prostate cancer, skin cancer, breast cancer, hepatocellular carcinoma, or cervical cancer.

[16] The method according to any one of [1] to

[15] , wherein the cancer is prostate cancer.

[17] The method according to any one of [1] to

[16] , wherein the cancer is drug-resistant prostate cancer.

[18] The method according to any one of [1] to

[17] , wherein the cancer is metastatic prostate cancer.

[19] The FABP5 inhibitor has the structure:

Chemical

[20] The compound has the structure I

change

change

[19] , wherein the alkyl is alkynyl, heteroalkyl, cycloheteroalkyl, aryl, heteroaryl, or heterocyclyl.

[21] The FABP5 inhibitor has the structure:

change

[22] The method according to any one of [1] to

[21] , wherein the taxane is paclitaxel, docetaxel, or cabazitaxel.

[23] The method according to any one of [1] to

[22] , wherein the taxane is docetaxel or cabazitaxel.

[24] The method according to any one of [1] to

[23] , wherein the taxane is docetaxel.

[25] The method according to any one of [1] to

[24] , wherein the taxane is cabazitaxel.

[26] The method according to [1], wherein the anticancer therapy is radiation therapy.

[27] The method according to

[26] , wherein the radiation therapy is external irradiation.

[28] The method according to

[26] , wherein the radiation therapy is brachytherapy.

[29] The method according to any one of [1] to

[28] , wherein the subject is a mammal.

[30] A pharmaceutical composition comprising a FABP5 inhibitor and a pharmaceutically acceptable carrier.

[31] The FABP5 inhibitor has the structure:

change

[30] ,

[32] The compound has structure I

change

change

[31] , wherein the alkyl is alkynyl, heteroalkyl, cycloheteroalkyl, aryl, heteroaryl, or heterocyclyl.

[33] The FABP5 inhibitor has the structure:

change

[30] ,

[34] The pharmaceutical composition according to any one of

[30] to

[33] , further comprising a taxane.

[35] The pharmaceutical composition according to

[34] , wherein the taxane is docetaxel or cabazitaxel.

[36] Use of a FABP5 inhibitor in combination with or as an add-on to an anti-cancer therapy in the treatment of a subject suffering from cancer, wherein the FABP5 inhibitor and the anti-cancer therapy are administered simultaneously, contemporaneously, or concomitantly.

[37] The FABP5 inhibitor has the structure:

change

[38] The use according to

[36] or

[37] , wherein the anticancer therapy is a taxane.

[39] The use according to

[36] or

[37] , wherein the anticancer therapy is radiation therapy.

[40] The use according to any one of

[36] to

[39] , wherein the cancer is prostate cancer.

[41] Use of a FABP5 inhibitor in the manufacture of a medicament for use in combination with or as an add-on to an anti-cancer therapy in the treatment of a subject suffering from cancer, wherein the FABP5 inhibitor and the anti-cancer therapy are administered simultaneously, contemporaneously, or concomitantly.

[42] A pharmaceutical composition for use in treating a subject suffering from cancer, comprising an amount of a FABP5 inhibitor and an amount of an anti-cancer therapy, wherein the FABP5 inhibitor and the anti-cancer therapy are administered simultaneously, contemporaneously, or concomitantly.

[43] The FABP5 inhibitor has the structure:

change

[44] The pharmaceutical composition according to

[42] or

[43] , wherein the anticancer therapy is a taxane.

[45] The pharmaceutical composition according to

[42] or

[43] , wherein the anticancer therapy is radiation therapy.

[46] The pharmaceutical composition according to any one of

[42] to

[45] , wherein the cancer is prostate cancer.

Claims

1. 1. A pharmaceutical composition comprising an effective amount of a FABP5 inhibitor for use in combination with or in addition to an anti-cancer therapy in the treatment of a subject suffering from cancer, wherein the FABP5 inhibitor has the structure: 【Chemistry 1】 (In the formula, R １ and R ２ are different and each is —C(═O)R １３ , -C(=O)OR １３ , —C(═O)O-alkyl-R １３ , —C(═O)NR １３ R １４ , -alkyl-C(=O)R １３ , -alkyl-C(=O)OR １３ , -alkyl-C(═O)NR １３ R １４ , -alkyl-OC(=O)OR １３ , -alkyl-OC(=O)R １３ , -alkyl-OR １３ , -alkyl-NR １３ R １４ , -alkyl-NHC(=O)R １３ , -alkyl-NHC(=O)OR １３ , -alkyl-NHC(=O)R １３ , -alkyl-NHC(=O)NR １３ R １４ , -alkyl-NHC(=S)NR １３ R １４ , -alkyl-NHC(=NR １３ ) NR １３ R １４ , -C(-OH)C(=O)OR １３ , -C(=O)C(=O)OR １３ or -C=C-R １３ and Here, R １３ and R １４ are each independently H, CF ３ , C １～１０ Alkyl, C ２～１０ Alkenyl, C ２～１０ alkynyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, substituted aryl, heteroaryl, heterocyclyl, or joined to form a cycloalkyl or heterocyclyl; R4, R ５ , R ６ , R ７ , R ９ , R １０ , R １１ and R １２ are each independently H, a halogen, or —NO ２ , -CN, -NHR １５ , -NR １５ R １６ , -SR １５ , -SO ２ R １５ , -OR １５ , -CO ２ R １５ , C.F. ３ , -alkyl-NR １５ R １６ , -alkyl-OR １５ , C １～１０ Alkyl, C ２～１０ Alkenyl, C ２～１０ alkynyl, aryl, heteroaryl, or heterocyclyl; R 3 and R 8 are each independently —OR 15 ; Here, R １５ and R １６ are each independently H, CF ３ , C １～１０ Alkyl, C ２～１０ Alkenyl, C ２～１０ alkynyl, heteroalkyl, cycloheteroalkyl, aryl, heteroaryl, or heterocyclyl or an enantiomer or racemate thereof; or a pharmaceutically acceptable salt thereof.

2. 1. A pharmaceutical composition comprising an effective amount of a FABP5 inhibitor for use in combination with or in addition to an anti-cancer therapy in the treatment of a subject suffering from cancer, wherein the FABP5 inhibitor has the structure: 【Chemistry 2】 (In the formula, R １ and R ２ are different and each is —C(═O)R １３ , -C(=O)OR １３ , —C(═O)O-alkyl-R １３ , —C(═O)NR １３ R １４ , -alkyl-C(=O)R １３ , -alkyl-C(=O)OR １３ , -alkyl-C(═O)NR １３ R １４ , -alkyl-OC(=O)OR １３ , -alkyl-OC(=O)R １３ , -alkyl-OR １３ , -alkyl-NR １３ R １４ , -alkyl-NHC(=O)R １３ , -alkyl-NHC(=O)OR １３ , -alkyl-NHC(=O)R １３ , -alkyl-NHC(=O)NR １３ R １４ , -alkyl-NHC(=S)NR １３ R １４ , -alkyl-NHC(=NR １３ ) NR １３ R １４ , -C(-OH)C(=O)OR １３ , -C(=O)C(=O)OR １３ or -C=C-R １３ and Here, R １３ and R １４ are each independently H, CF ３ , C １～１０ Alkyl, C ２～１０ Alkenyl, C ２～１０ alkynyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, heterocyclyl, or joined to form a cycloalkyl or heterocyclyl; R ４ , R ５ , R ６ , R ７ , R ９ , R １０ , R １１ and R １２ are each independently H, a halogen, or —NO ２ , -CN, -NHR １５ , -NR １５ R １６ , -SR １５ , -SO ２ R １５ , -OR １５ , -CO ２ R １５ , C.F. ３ , -alkyl-NR １５ R １６ , -alkyl-OR １５ , C １～１０ Alkyl, C ２～１０ Alkenyl, C ２～１０ alkynyl, aryl, heteroaryl, or heterocyclyl; R 3 and R 8 are each independently —OR 15 ; Here, R １５ and R １６ are each independently H, CF ３ , C １～１０ Alkyl, C ２～１０ Alkenyl, C ２～１０ alkynyl, heteroalkyl, cycloheteroalkyl, aryl, heteroaryl, or heterocyclyl or an enantiomer or racemate thereof; or a pharmaceutically acceptable salt thereof.

3. 1. A pharmaceutical composition comprising an effective amount of a FABP5 inhibitor for use in combination with or in addition to an anti-cancer therapy in the treatment of a subject suffering from cancer, wherein the FABP5 inhibitor has the structure: 【Transformation 3】 (In the formula, R １ and R ２ are different and each is —C(═O)R １３ , -C(=O)OR １３ , —C(═O)O-alkyl-R １３ , —C(═O)NR １３ R １４ , -alkyl-C(=O)R １３ , -alkyl-C(=O)OR １３ , -alkyl-C(═O)NR １３ R １４ , -alkyl-OC(=O)OR １３ , -alkyl-OC(=O)R １３ , -alkyl-OR １３ , -alkyl-NR １３ R １４ , -alkyl-NHC(=O)R １３ , -alkyl-NHC(=O)OR １３ , -alkyl-NHC(=O)R １３ , -alkyl-NHC(=O)NR １３ R １４ , -alkyl-NHC(=S)NR １３ R １４ , -alkyl-NHC(=NR １３ ) NR １３ R １４ , -C(-OH)C(=O)OR １３ , -C(=O)C(=O)OR １３ or -C=C-R １３ and Here, R １３ and R １４ are each independently H, CF ３ , C １～１０ Alkyl, C ２～１０ Alkenyl, C ２～１０ alkynyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, heterocyclyl, or joined to form a cycloalkyl or heterocyclyl; R ４ , R ５ , R ６ , R ７ , R ９ , R １０ , R １１ and R １２ are each independently H, a halogen, or —NO ２ , -CN, -NHR １５ , -NR １５ R １６ , -SR １５ , -SO ２ R １５ , -OR １５ , -CO ２ R １５ , C.F. ３ , -alkyl-NR １５ R １６ , -alkyl-OR １５ , C １～１０ Alkyl, C ２～１０ Alkenyl, C ２～１０ alkynyl, aryl, heteroaryl, or heterocyclyl; R 3 and R 8 are each independently —OR 15 ; Here, R １５ and R １６ are each independently H, CF ３ , C １～１０ Alkyl, C ２～１０ Alkenyl, C ２～１０ alkynyl, heteroalkyl, cycloheteroalkyl, aryl, heteroaryl, or heterocyclyl or an enantiomer or racemate thereof; or a pharmaceutically acceptable salt thereof.

4. 1. A pharmaceutical composition comprising an effective amount of a FABP5 inhibitor for use in combination with or in addition to an anti-cancer therapy in the treatment of a subject suffering from prostate cancer, wherein the FABP5 inhibitor has the structure: 【Chemistry 4】 (In the formula, R １ and R ２ are different and each is —C(═O)R １３ , -C(=O)OR １３ , —C(═O)O-alkyl-R １３ , —C(═O)NR １３ R １４ , -alkyl-C(=O)R １３ , -alkyl-C(=O)OR １３ , -alkyl-C(═O)NR １３ R １４ , -alkyl-OC(=O)OR １３ , -alkyl-OC(=O)R １３ , -alkyl-OR １３ , -alkyl-NR １３ R １４ , -alkyl-NHC(=O)R １３ , -alkyl-NHC(=O)OR １３ , -alkyl-NHC(=O)R １３ , -alkyl-NHC(=O)NR １３ R １４ , -alkyl-NHC(=S)NR １３ R １４ , -alkyl-NHC(=NR １３ ) NR １３ R １４ , -C(-OH)C(=O)OR １３ , -C(=O)C(=O)OR １３ or -C=C-R １３ and Here, R １３ and R １４ are each independently H, CF ３ , C １～１０ Alkyl, C ２～１０ Alkenyl, C ２～１０ alkynyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, heterocyclyl, or joined to form a cycloalkyl or heterocyclyl; R ４ , R ５ , R ６ , R ７ , R ９ , R １０ , R １１ and R １２ are each independently H, a halogen, or —NO ２ , -CN, -NHR １５ , -NR １５ R １６ , -SR １５ , -SO ２ R １５ , -OR １５ , -CO ２ R １５ , C.F. ３ , -alkyl-NR １５ R １６ , -alkyl-OR １５ , C １～１０ Alkyl, C ２～１０ Alkenyl, C ２～１０ alkynyl, aryl, heteroaryl, or heterocyclyl; R 3 and R 8 are each independently —OR 15 ; Here, R １５ and R １６ are each independently H, CF ３ , C １～１０ Alkyl, C ２～１０ Alkenyl, C ２～１０ alkynyl, heteroalkyl, cycloheteroalkyl, aryl, heteroaryl, or heterocyclyl or an enantiomer or racemate thereof; or a pharmaceutically acceptable salt thereof.

5. 1. A pharmaceutical composition comprising an effective amount of a FABP5 inhibitor for use in combination with or in addition to an anti-cancer therapy in the treatment of a subject suffering from cancer, wherein the FABP5 inhibitor has the structure: 【Transformation 5】 (In the formula, R １ and R ２ are different and each is —C(═O)R １３ , -C(=O)OR １３ , —C(═O)O-alkyl-R １３ , —C(═O)NR １３ R １４ , -alkyl-C(=O)R １３ , -alkyl-C(=O)OR １３ , -alkyl-C(═O)NR １３ R １４ , -alkyl-OC(=O)OR １３ , -alkyl-OC(=O)R １３ , -alkyl-OR １３ , -alkyl-NR １３ R １４ , -alkyl-NHC(=O)R １３ , -alkyl-NHC(=O)OR １３ , -alkyl-NHC(=O)R １３ , -alkyl-NHC(=O)NR １３ R １４ , -alkyl-NHC(=S)NR １３ R １４ , -alkyl-NHC(=NR １３ ) NR １３ R １４ , -C(-OH)C(=O)OR １３ , -C(=O)C(=O)OR １３ or -C=C-R １３ and Here, R １３ and R １４ are each independently H, CF ３ , C １～１０ Alkyl, C ２～１０ Alkenyl, C ２～１０ alkynyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, heterocyclyl, or joined to form a cycloalkyl or heterocyclyl; R ４ , R ５ , R ６ , R ７ , R ９ , R １０ , R １１ and R １２ are each independently H, a halogen, or —NO ２ , -CN, -NHR １５ , -NR １５ R １６ , -SR １５ , -SO ２ R １５ , -OR １５ , -CO ２ R １５ , C.F. ３ , -alkyl-NR １５ R １６ , -alkyl-OR １５ , C １～１０ Alkyl, C ２～１０ Alkenyl, C ２～１０ alkynyl, aryl, heteroaryl, or heterocyclyl; R 3 and R 8 are each independently —OR 15 ; Here, R １５ and R １６ are each independently H, CF ３ , C １～１０ Alkyl, C ２～１０ Alkenyl, C ２～１０ alkynyl, heteroalkyl, cycloheteroalkyl, aryl, heteroaryl, or heterocyclyl or an enantiomer or racemate thereof; or a pharmaceutically acceptable salt thereof, wherein said anti-cancer therapy is docetaxel or cabazitaxel.

6. 6. The pharmaceutical composition of any one of claims 1 to 5, comprising periodically administering to the subject amounts of the FABP5 inhibitor and the anti-cancer therapy, said amounts, when taken together, are effective to treat the subject.

7. 6. The pharmaceutical composition of any one of claims 1 to 5, wherein the amount of the FABP5 inhibitor and the amount of the anti-cancer therapy, when administered together, are more effective to treat the subject than when the same amount of each agent is administered alone.

8. The pharmaceutical composition of any one of claims 1 to 5, wherein the subject is undergoing the anticancer therapy prior to initiation of FABP5 inhibitor therapy.

9. The pharmaceutical composition of any one of claims 1 to 5, wherein the subject is receiving the FABP5 inhibitor therapy prior to initiation of the anticancer therapy.

10. The pharmaceutical composition of any one of claims 1 to 5, wherein the FABP5 inhibitor and the anti-cancer therapy are administered sequentially.

11. The pharmaceutical composition of any one of claims 1 to 5, wherein the FABP5 inhibitor is administered first, followed by the anti-cancer therapy.

12. The pharmaceutical composition of any one of claims 1 to 5, wherein the anti-cancer therapy is administered first, followed by the FABP5 inhibitor.

13. The pharmaceutical composition of any one of claims 1 to 5, wherein the FABP5 inhibitor and the anti-cancer therapy are administered simultaneously.

14. The pharmaceutical composition according to any one of claims 1 to 5, wherein the FABP5 inhibitor is administered orally, intravenously, or intraperitoneally.

15. The pharmaceutical composition of any one of claims 1 to 4, wherein the anti-cancer therapy is a taxane.

16. 16. The pharmaceutical composition of claim 15, wherein the taxane is administered intravenously or intraperitoneally.

17. The pharmaceutical composition according to any one of claims 1 to 5, wherein the cancer expresses FABP5.

18. The pharmaceutical composition according to any one of claims 1 to 5, wherein the cancer overexpresses FABP5.

19. The pharmaceutical composition according to any one of claims 1 to 3 and 5, wherein the cancer is prostate cancer, skin cancer, breast cancer, hepatocellular carcinoma or cervical cancer.

20. 20. The pharmaceutical composition of claim 19, wherein the cancer is prostate cancer.

21. 21. The pharmaceutical composition of claim 20, wherein the cancer is drug-resistant prostate cancer.

22. 20. The pharmaceutical composition of claim 19, wherein the cancer is metastatic prostate cancer.

23. The FABP5 inhibitor has the structure: 【Transformation 6】 or a pharmaceutically acceptable salt thereof.

24. 16. The pharmaceutical composition of claim 15, wherein the taxane is paclitaxel, docetaxel, or cabazitaxel.

25. 25. The pharmaceutical composition of claim 24, wherein the taxane is docetaxel or cabazitaxel.

26. 26. The pharmaceutical composition of claim 25, wherein the taxane is docetaxel.

27. 26. The pharmaceutical composition of claim 25, wherein the taxane is cabazitaxel.

28. The pharmaceutical composition of any one of claims 1 to 27, wherein the subject is a mammal.

29. 29. The pharmaceutical composition of claim 28, wherein the mammal is a human.

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