Poster #LBA041: AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer, October 7-10, 2021
The DNA damage response (DDR) is a complex cellular network that acts as a cell defense mechanism and exerts signal for repair of DNA lesions. It repairs different types of DNA damage such as single-strand (ssDNA) breaks, DNA inter-strand crosslinks and double strand breaks (DSB) caused by endogenous and exogenous factors. These damages are mainly repaired by homologous recombination (HR) repair, and non-homologous end joining (NHEJ). DNA double-strand breaks (DSBs) are the most severe DNA damage and predominantly repaired by HR. As the DDR pathway is critical for tumorigenesis, a high degree of interest has been generated in the recent past to target this network. RAD51 is one of the pivotal enzymes for DNA double-strand break repair by the HR pathway.
While PARP inhibitors are extensively used for BRCA2 mutated cancers, their responses in BRCA2 WT is limited. Targeting RAD51 will open a new avenue to treat BRCA2 WT cancer patients. BRCA2 interaction with RAD51 is a prerequisite for RAD51 nuclear translocation to exert its function by binding to DNA. The disruption of this interaction leads to inhibition of DNA repair and in turn inhibits proliferation and tumor growth. Disruption of RAD51:BRCA2 interaction leads to BRCAness in an otherwise BRCA2 WT background and is thus expected to have synergy with PARP1 inhibitors. We report the identification of novel and potent RAD51 inhibitors which disrupt the RAD51:BRCA2 interaction.
Our hit compounds show anticancer activity in relevant cancer cell lines across various indications. Further, our compounds inhibit RAD51 nuclear translocation upon induction of exogenous DNA damage. Multiple series have been identified, with a good SAR trend and correlating well with cell based and PD activity. Further profiling of these compounds is ongoing.
