Targeting Rad51-Brca2 Interaction to Induce Synthetic Lethality with Olaparib in Pancreatic Cancer: Development of a Novel Series of Phenyl Furan-Quinoline-Carboxylic Acids

Synthetic lethality has proven to be a tactical paradigm to design synergistic combinations of anticancer drugs. Indeed, we can simultaneously inhibit two synthetic lethal targets to kill cancer cells without the requirement of specific pre-existing mutations. In line with our previous works, we leveraged BRCA2 and PARP as synthetic lethal pair of targets. Specifically, we consolidated the use of small molecule inhibitors of RAD51-BRCA2 protein-protein interaction (PPI) as inducers of a BRCAness phenotype that sensitizes BRCA2-functional cancer cells to PARP inhibitors. Through virtual screening, we identified a phenyl furan-carboxyquinoline hit compound 1 that we used as a starting point for our chemical efforts. We built a series of analogues and established a pipeline to select RAD51-BRCA2 PPI inhibitors that impair in-cell homologous recombination (HR) and induce a synthetic lethal phenotype in combination with PARP inhibitor in pancreatic cancer cells BxPC-3. This led to 6-methoxy-quinoline derivative 19, a micromolar RAD51-BRCA2 PPI inhibitor that impairs HR and synergizes with olaparib in a dose-response manner, triggering SL in 2D and 3D spheroids BxPC-3. The impairment of HR by 19 was also confirmed by the decrease in RAD51 nuclear foci and the increase in γ-H2AX and micronuclei, upon DNA damage. Additionally, 19 was effective with olaparib in a different pancreatic cancer line, HPAC. Moreover 19 showed no toxicity in pancreatic normal cells, making it an eligible starting point for future drug discovery efforts.