Abstract B064: ONECUT2 inhibition, a potential treatment for lethal prostate cancer

Abstract

Abstract Prostate cancer (PCa) is the most common cancer and the second most lethal cancer in men, claiming over 30,000 lives each year in the US alone. These PCa patient deaths are typically due to castration-resistant PCa (CRPC) which is resistant to androgen deprivation therapy, androgen receptor signaling inhibitors, and chemotherapies. Our group and others have shown that the transcription factor ONECUT2 (OC2) is a critical driver of CRPC. We have discovered a low molecular weight inhibitor of OC2 (OC2i), known as CSRM617, which inhibits metastatic PCa in cell culture (IC50 of 5-15 uM depending on cell line used) and effectively treats xenograft CRPC tumors in mouse models. We have developed a large series of these OC2i based on the CSRM617 scaffold. A thorough understanding of how these OC2i bind to and inhibit OC2 function are imperative to developing them into a clinically viable treatment option. Our recent work shows CSRM617 binds Fe and that this Fe:CSRM617 complex is necessary in order to inhibit OC2 binding of DNA. We have solved the crystal structure of OC2 bound to its conjugate DNA response element, demonstrating their atomic-level interactions. We are working towards solving a crystal structure of these OC2i bound to OC2 in order understand their specific interactions and make rational modifications to the chemical scaffold for improvements in binding affinity and pharmacokinetic properties. Citation Format: Brad Gallent, Chen Qian, Avradip Chatterjee, Madhusudhanarao Katiki, Ramachandran Murali, Michael R Freeman. ONECUT2 inhibition, a potential treatment for lethal prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr B064.