Abstract 1777: OST11098, an orally available and selective Cyp11A1 inhibitor for the treatment of castration-resistant prostate cancer (CRPC) with next-generation hormone agents (NHAs) resistance

Abstract Next-generation hormone agents (NHAs) such as abiraterone and enzalutamide have become standard treatments for castration-resistant prostate cancer (CRPC), significantly prolonging patient survival. However, resistance to NHAs inevitably develops, presenting a critical and unmet clinical challenge. Inhibition of CYP11A1 disrupts the entire biosynthesis pathway of androgens and other steroids by blocking the formation of pregnenolone. This mechanism halts the activation of the androgen receptor (AR) axis, thereby preventing further cancer progression and potentially overcoming NHAs resistance in heavily pretreated CRPC patients.In this study, we introduce OST11098, a newly identified, orally bioavailable, selective, and potent CYP11A1 inhibitor with demonstrated anti-tumor efficacy against NHA resistance. OST11098 displays favorable pharmacokinetic and safety profiles. In vitro, it effectively inhibited pregnenolone biosynthesis at low nanomolar concentrations in the H295R adrenocortical carcinoma cell line, leading to a rapid and complete blockade of all measured downstream steroid hormones. When administered orally, OST11098 showed consistent, dose-dependent pharmacokinetic/pharmacodynamic (PK/PD) correlations in adult non-castrated male mice, successfully inhibiting the biosynthesis of androgen receptor (AR) activators. In a VCaP CRPC xenograft mouse model, OST11098 demonstrated significant anti-tumor efficacy. Moreover, an engineered LNCaP CRPC xenograft mouse model with NHA resistance was successfully established and evaluated for its response to OST11098 treatment, providing compelling preclinical evidence supporting the use of CYP11A1 inhibitors as a promising strategy for managing NHA-resistance.Overall, our studies demonstrated OST11098 as a highly potent and selective CYP11A1 inhibitor with great PK properties, clean safety profiles, and significant anti-tumor activity for the treatment of CRPC. These promising preclinical results strongly support the potential of OST11098 to address unmet needs in CRPC treatment, justifying its further clinical development. Citation Format: Fangrui Wu, Lisheng Deng, zhixiong Ma, Zhenyao Lu, Gabriel Deng. OST11098, an orally available and selective Cyp11A1 inhibitor for the treatment of castration-resistant prostate cancer (CRPC) with next-generation hormone agents (NHAs) resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1777.