New RAD51 Inhibitors to Target Homologous Recombination in Human Cells

Targeting DNA repair proteins with small-molecule inhibitors became a proven anti-cancer strategy. Previously, we identified an inhibitor of a major protein of homologous recombination (HR) RAD51, named B02. B02 inhibited HR in human cells and sensitized them to chemotherapeutic drugs in vitro and in vivo. Here, using a medicinal chemistry approach, we aimed to improve the potency of B02. We identified the B02 analog, B02-isomer, which inhibits HR in human cells with significantly higher efficiency. We also show that B02-iso sensitizes triple-negative breast cancer MDA-MB-231 cells to the PARP inhibitor (PARPi) olaparib.

Automated summary

By using a medicinal chemistry approach, the potency of B02 in inhibiting HR was improved and a B02 analog, B02-isomer, was discovered to synergize with PARPi in triple-negative breast cancer cells.