Prostate cancer (PCa) is one of the most common malignancies diagnosed among men and is the second leading cause of cancer-related death. Despite recent advancements in early diagnosis of PCa, androgen deprivation therapy (ADT) remains the most common treatment of PCa. Docetaxel (DTX) and Cabazitaxel (CTX) are two of the most extensively used drugs for mCRPC. However, there is a clear medical need for newer and more efficacious therapies for mCRPC. While normal prostate cells lack FABP5 expression, FABP5 is overexpressed in metastasized prostate cancer cells. FABP5 chaperones fatty acids to PPARs, which leads to the upregulation of proangiogenic factors (i.e., VEGF, MMP), resulting in cell survival and metastatic phenotype. We reported that the knockout of FABP5 significantly reduced tumor growth and metastasis in vivo. The study also recognized that the PPARγ signaling pathway highly relies on the lipid ligand transportation by FABP5 in promoting PCa growth and metastasis in vitro and in vivo. The critical role and upregulation of FABP5 in PCa make FABP5 a druggable target for mCRPC. Our previous study revealed the anti-PC potential of a truxillic acid monoester (TAME) - based FABP5 inhibitor and its synergism with DTX and CTX. In the present work, we performed an extensive SAR study, which led to the identification of more potent and selective TAME-based FABP5 inhibitors against metastatic human (PC3) and mCRPC rodent (RCaP) cell lines. It is also worth noting that TAME-based FABP5 inhibitors exhibited no systemic toxicity so far in vivo. We also investigated possible synergism between selected FABP5 inhibitors with several anticancer drugs and found that a combination with a topoisomerase I inhibitor, topotecan, was effective. Especially, the combination of α-SB-FI-1043 with topotecan was found to be highly synergistic, expanding the therapeutic window of topotecan remarkably. Those findings and indications will be discussed.

Truxillic acid monoesters as novel fatty acid binding protein 5 inhibitors treating metastatic castration-resistant prostate cancer

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