Abstract 6369: Discovery of potent, orally bioavailable, brain penetrant RAD51 inhibitor as an anti-cancer agent

Abstract

Abstract Proliferating cells undergo DNA damage, and this is more pronounced in cancer cells due to their high rate of proliferation. Cancer cells are thus more dependent on the DNA damage repair pathway for their survival. Double-strand breaks (DSBs) are amongst the most severe type of DNA damage and are predominantly repaired by homologous recombination (HR) in an error-free manner. RAD51 is a pivotal recombinase for DSB repair by the HR pathway. Binding of RAD51 with BRCA2 followed by its nuclear translocation, is one of the key repair mechanisms for RAD51 mediated DSB repair. We have identified novel and potent RAD51 inhibitors disrupting the RAD51:BRCA2 interaction, which can address BRCA2 WT patient population. Upon induction of exogenous DNA damage, our compounds inhibit nuclear RAD51 foci formation and demonstrate sustained γH2AX accumulation in the nucleus, suggesting persistent DNA damage. Our orally bioavailable & brain penetrant lead compound shows anti-proliferative activity in multiple BRCA2 WT cancer cell lines across various indications, and excellent synergy when combined with PARP1 inhibitors such as Olaparib. Further, in a wound healing assay, treatment with our lead compound inhibits cell migration in a dose-dependent manner. TNBC patients with extensive brain metastasis have limited treatment options. Thus, a brain penetrant RAD51 inhibitor could provide a novel treatment option in this setting. Citation Format: Sanjita Sasmal, Sukanya Patra, Venkatesham Boorgu, Shankar Chithaluri, Mahesh Yanamadra, Deepika Hiremath, Hemashankar Pathange, Sandeep M. Girme, Amitkumar Pawar, Rutuja Narayan Shinde, Nilanjan Samanta. Discovery of potent, orally bioavailable, brain penetrant RAD51 inhibitor as an anti-cancer agent [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6369.