Abstract 6881: Discovery of ACE-232: a novel and highly potent non-steroidal CYP11A1 inhibitor

Abstract CYP11A1 is the first and rate-limiting enzyme in steroid hormone biosynthesis, catalyzing the conversion of cholesterol to pregnenolone and isocaproic aldehyde. Inhibition of this enzyme blocks the entire steroid hormone biosynthesis pathway, including androgens and their precursors, which activate the androgen receptor (AR) and promote prostate cancer growth. Targeting CYP11A1 has led to therapies like ODM-208 (MK-5684), which shows antitumor activity in heavily pretreated mCRPC patients, especially those with AR ligand binding domain (LBD) mutations. Here we report the discovery of ACE-232, a novel, highly potent, and selective CYP11A1 inhibitor. ACE-232 is significantly more potent than ODM-208 (>15x) in inhibiting CYP11A1 in human adrenal adenocarcinoma H295R cells, with an IC50 of 0.17 nM compared to ODM-208's IC50 of 2.82 nM. Additionally, ACE-232 demonstrates superior potency (>10x) in suppressing testosterone biosynthesis in H295R cells. Preclinical pharmacokinetic studies show that ACE-232 has significantly lower clearance and a longer half-life across multiple species (mouse, rat, and dog), resulting in a flatter pharmacokinetic (PK) curve compared to ODM-208. Together, these properties may enable sustained target engagement with once-daily dosing while minimizing hormone level fluctuations in patients. In castrated mouse models, ACE-232 showed equal or superior efficacy in inhibiting tumor growth at 0.3 mg/kg QD in both VCaP and enzalutamide-resistant xLNCaP models, compared to ODM-208 at 30 mg/kg BID. Furthermore, in a non-castrated mouse model, ACE-232 showed significant efficacy at 1.5 mg/kg BID, whereas ODM-208 at 30 mg/kg BID did not. ACE-232 also demonstrates favorable ADME properties suitable for drug development. In a safety panel screening across 93 targets at 5 µM, ACE-232 exhibited minimal off-target effects. GLP toxicology studies demonstrated a wide safety margin in both rats and dogs, with primary effects observed in the endocrine and reproductive organs, consistent with CYP11A1 inhibition. Based on these findings, an IND filing for ACE-232 with the FDA is planned for December 2024. Citation Format: Kuo-Long Yu, Hongbin Yuan, Sanjeev Kumar, Kai Kang, Wenming Li, Manhua Li, Weitao Pan, Wenqian Li, Junmei Wang, Zhiming Wen, Genshi Zhao, Tinggui Yin. Discovery of ACE-232: a novel and highly potent non-steroidal CYP11A1 inhibitor [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 6881.