Serendipity meets synergism: differential enantiomer activities of a RAD51-BRCA2 disruptor towards a more robust synthetic lethality in pancreatic cancer

Abstract The innovative framework of a fully small molecule-induced synthetic lethality gained increasing attention for its promising application in the selective eradication of cancer cells. Disrupting the interaction between BRCA2 and RAD51, key players in DNA repair by homologous recombination (HR), represents an interesting option within the synthetic lethality paradigm. We previously showed that combining the PARP inhibitor (PARPi) olaparib with the BRCA2-RAD51 disruptor RS-35d, a racemic dihydroquinolone pyrazoline-derivative previously synthetized by us, was efficient in tackling pancreatic ductal adenocarcinoma (PDAC). To deepen our knowledge on this approach, we investigated RS-35d mode of action by characterising the single contribution of the purified two enantiomers, R-35d and S-35d respectively. RS-35d racemate was unveiled to possess a built-in synthetic lethal profile, falling within the paradigm of “within-pathway synthetic lethality”. This opens the way for novel anticancer synthetic lethality strategies towards more robust personalised medicine approaches for unmet medical needs like BRCA-competent and PARP-resistant PDAC.