Targeting DNA damage response (DDR) pathway has been proposed as an approach for amplifying tumor-specific replicative lesions. RAD51 plays a central role in the DDR process, and thus represents a promising anti-tumor target. We here report the discovery of a series of next generation RAD51 inhibitors that can prevent RAD51 foci formation. The lead compounds dramatically impaired human cancer cell growth, induced cell cycle arrest in S-phase, and resulted in elevated γH2AX. Furthermore, cancer cells became sensitized to chemotherapy and other DDR inhibitors. Dosed either as a single agent or in combination with cisplatin, the compounds significantly inhibited tumor growth in vivo. By upregulating ATR-CHK1 signaling, the RAD51 inhibitors increased surface PD-L1 levels in various tumor cells, suggesting a potential combination of RAD51 inhibitors with PD-1/PD-L1 blockade. Overall, our findings provide the preclinical rationale to explore RAD51 inhibitors as monotherapy or in combination with chemotherapy, immunotherapy or DDR-targeting therapy in cancer treatment.

Targeting DNA damage response (DDR) pathways has been proposed as an approach for amplifying tumor-specific replicative lesions. RAD51 plays a central role in the DDR pathway, and thus represents a promising anti-tumor target. We here report the discovery of a series of next generation RAD51 inhibitors that can prevent RAD51 foci formation and particularly, a pre-clinical candidate molecule SCR-6992 with potent anti-tumor efficacies and desirable pre-clinical development drug properties. SCR-6992 exhibits remarkable anti-proliferative potency in human lymphoma Daudi cells in vitro (IC50 = 12 nM) while has no inhibitory effect in normal human cells. The combination of SCR-6992 with chemotherapeutic agents or DDR-targeting drugs produces synergistical anti-cancer response in lymphoma and solid tumor cell lines. Furthermore, SCR-6992 significantly inhibits tumor growth in Daudi xenograft tumor model with the tumor regression observed when dosed orally at 80 mg/kg/day. SCR-6992 also shows acceptable translational drug properties and pharmacokinetic profiles in both rodents and dogs. SCR-6992 was well tolerated in rats and dogs in 14-day dose range finding studies without noted hematological or gastrointestinal toxicities, when dosed up to 200 mg/kg and 40 mg/kg, respectively. Taken together, SCR-6992 demonstrates as an effective RAD51 inhibitor with encouraging anti-tumor activities and favorable development drug properties. The clinical development plans of SCR-6992 have been formulated for hematologic malignancies and solid tumors. Citation Format: Peng Gu, Liting Xue, Ping Chen, Wenjing Li, Ya Geng, Feng Zhou, Guimei Yang, Xiaohong Hou, Chunyan Zhao, Wenqing Yang, Renhong Tang. Discovery of a novel RAD51 inhibitor SCR-6992 targeting homologous recombination pathways in cancer [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 5441.