Targeting RAD51-BRCA2 Interaction to Enhance Synthetic Lethality with Olaparib in Pancreatic Cancer: Development of a Novel Phenyl Furan-Quinoline-Carboxylic Acid Series

Synthetic lethality has proven to be a tactical paradigm to design synergistic anticancer drug combinations. In this context, we leveraged BRCA2 and PARP as a synthetic lethal target pair to consolidate the use of small molecule inhibitors of RAD51-BRCA2 protein-protein interaction as inducers of the BRCAness phenotype that sensitizes BRCA2-functional cancer cells to PARP inhibitors. Starting from compound 1, a phenyl furan-carboxyquinoline, we developed a series of analogues, leading to derivative 19. This compound effectively inhibits RAD51-BRCA2 interaction, impairs homologous recombination, and synergizes with olaparib in BxPC-3 pancreatic cancer cells, inducing synthetic lethality in both 2D and 3D spheroids. Additionally, 19 showed efficacy in human pancreatic cancer cells and no toxicity in normal pancreatic cells, positioning it as an early tool compound and a starting point for further optimization.