Design and synthesis of RAD51-BRCA2 disruptors to inhibit homologous recombination and synergize with Olaparib as new anticancer drug discovery concept

Homologous recombination (HR) is an error-free DNA repair pathway triggered in the presence of DNA double-strand breaks (DSBs). BRCA2 protein plays a key role in HR by recruiting RAD51, the ATP-dependent recombinase that directly initiates DSBs repair. Because cancer cells rely on efficient HR activity, the inhibition of BRCA2-RAD51 protein-protein interaction (PPI) represents an attractive strategy for the development of novel therapeutics. In this context, we recently proposed a new anticancer drug discovery concept, which combines RAD51-BRCA2 disruptors with the PARP inhibitor Olaparib.1 Indeed, according to our working hypothesis, administering RAD51-BRCA2 disruptors to BRCA2-functional cancer cells would chemically mimic the enhanced sensitivity to Olaparib observed in BRCA2-defective oncology patients, leading to a synthetic lethal effect.2 Targeting PPI is an attractive strategy for designing innovative drugs. However it was proven to be challenging due to the typical protein-protein large and flat interfaces3. In depth studies of the two protein structures allowed identifying two PPI critical “hotspots” on RAD51 surface, zone I and II, as suitable targets for the design of small molecule PPI inhibitors. Following a structure-based approach focused on zone I, a virtual screening campaign allowed us to identify a triazole based hit compound 1 that showed to inhibit BRCA2-RAD51 PPI in biochemical assay.2 To discover more effective compounds and depict general structure-activity relationship (SAR) studies, the chemical space around 1 was explored by optimizing a general synthetic strategy and building a library of new triazole analogues (Figure 1).1,2 As proof of principle, compound 2 proved to inhibit HR and increase the response to Olaparib in pancreatic cancer cells expressing a functional BRCA2, supporting the idea that small organic molecules can mimic genetic mutations. To promote sustainable chemistry, we privileged protocols that exploit microwave-assisted synthesis.