SAT-317 Design and Evaluation of novel CYP17A1 Inhibitors: Potential Therapeutic Agents for Castration-Resistant Prostate Cancer

Abstract Disclosure: J. Yakubu: None. T.M. Wróbel: None. A. Grudzińska: None. T. du Toit: None. K. Sharma: None. J.C. Harrington: None. N. Dycha: None. F. Björkling: None. F.S. Jørgensen: None. A.V. Pandey: None. Castration-resistant prostate cancer (CRPC) remains a significant clinical challenge due to the persistence of androgen synthesis, even in the absence of testicular testosterone. This ongoing steroidogenesis is primarily driven by CYP17A1, an enzyme essential for androgen biosynthesis. Although CYP17A1 inhibitors like abiraterone have shown efficacy, drug resistance and adverse effects limit their clinical success. This study aims to develop novel, potent CYP17A1 inhibitors to address these challenges.Starting from a previously identified hit compound, we synthesized a series of analogs and encountered an unanticipated di-cyano derivative as a side product, which demonstrated enhanced potency against CYP17A1 compared to abiraterone. These compounds were evaluated for their ability to inhibit CYP17A1 activity using the human adrenal NCI-H295R cell line, which is a reliable model for studying steroidogenesis. Biological assays confirmed that these compounds significantly disrupted CYP17A1 enzymatic activity and altered steroid profiles, with compound 11 showing the highest potency (IC50 = 4 nM). Compound 14, also potent, emerged as a valuable template for further development.SAR analysis revealed that compounds containing an indole moiety (5 and 11) were more potent than those with a benzotriazole fragment (1 and 10), suggesting indole is a preferred structure for CYP17A1 inhibition. These findings were supported by LC-MS analysis of steroid profiles from adrenal NCI-H295R cells, where compound 11 was the most effective in reducing both hydroxylase and lyase activities of CYP17A1.In prostate cancer cell lines (LNCaP and VCaP), compounds 5 and 6 significantly reduced cell viability, highlighting their potential to impair androgen-dependent tumour growth. Interestingly, compound 11, despite its potent enzyme inhibition, did not show high cytotoxicity in these cell lines, indicating a selective mechanism of action. Importantly, none of the compounds exhibited significant cytotoxicity in normal prostate cells (RWPE-1), suggesting a favourable therapeutic window.These results show the potential of novel CYP17A1 inhibitors, particularly compound 11, in targeting steroidogenesis and inhibiting CRPC progression. Presentation: Saturday, July 12, 2025