Fatty acid binding protein 5 inhibitors as novel anticancer agents against metastatic castration-resistant prostate cancer

Abstract

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 metastatic castration-resistant prostate cancer (mCRPC). However, there is a clear medical need for newer and more efficacious therapies for CRPC. FABP5 is overexpressed in prostate cancer cells and chaperones fatty acids to PPARs, which leads to the upregulation of proangiogenic factors, resulting in cell survival and metastasis. The critical role and upregulation of FABP5 in PCa make FABP5 an excellent druggable target for CRPC. We reported a promising anti-PCa activity of truxillic acid monoester (TAME)-based FABP5 inhibitors (SB-FIs) and their synergy with DTX and CTX in vitro and in vivo against PC-3 cells and PC-3 tumor xenografts. In the present work, we performed an extensive SAR study on the potencies of 2nd- and 3rd-generation SB-FIs against PC-3 and RCaP cell lines. RCaP is a mouse PCa cell line, resistant to anti-androgen and first-line taxane chemotherapies, and shows a high level of the Fabp5-gene. This SAR study led to the identification of a number of 3rd-generation SB-FIs with strong cytotoxicity against these two PCa cell lines. Cell cycle analysis of selected SB-FIs revealed a clear evolution of apoptotic potency in the 1st-, 2nd- and 3rd-generation SB-FIs. Since taxanes, DTX and CTX, are ineffective against RCaP cell line, we selected a topoisomerase I inhibitor, topotecan (TPT) as a replacement for taxanes. We screened the library of SB-FIs for synergy with TPT and identified 3 SB-FIs (L3, α-11 and α-4), exhibiting strong synergy, which could remarkably expand the therapeutic window of TPT.