Design and synthesis of BRCA2-RAD51 disruptors to induce synthetic lethality in cancer treatment

Synthetic lethality is a lethal phenotype arising from the combination of two specific gene mutations, which are harmless when they occur individually (fig.1a). [1] Targeting a pair of synthetic lethal genes represents an attractive opportunity in pharmaceutical field for the development of novel therapeutics. One straightforward application of synthetic lethality in anticancer drug development is the use of Olaparib, the first approved PARP inhibitor, in BRCA2-defective oncology patients. BRCA2 and PARP are proteins involved in two independent mechanisms of DNA repair. PARP is important for repairing single-strand breaks, whereas BRCA2 is essential for repairing double-strand breaks by homologous recombination (HR) as it recruits protein RAD51 from the cytosol and stabilizes the complex RAD51-DNA. [2] In this context to develop a new anticancer drug discovery concept, we explored the possibility to trigger a fully-small-molecule-induced synthetic lethality combining protein-protein (PP) BRCA2 RAD51 disruptors with Olaparib. Targeting PP interactions is an attractive strategy for designing innovative drugs. However it was proven to be challenging due to the typical PP large and flat interfaces. [3] BRCA2-RAD51 PPI is mediated by two critical “hotspots” on RAD51 surface, zone I and II, which can be suitable targets for the development of small molecule PPI inhibitors. [2] Following a structure-based approach, we initially performed a virtual screening campaign, focusing on zone I. The triazole compound ARN19793 was identified as the best candidate as it proved to increase the response to Olaparib in pancreatic cancer cells expressing a functional BRCA2. [2] To explore the chemical space around ARN19793, structure-activity relationship (SAR) studies were performed, optimizing a synthetic strategy to build a library of analogues with preserved triazole core (Fig.1b). To promote sustainable chemistry, I privileged protocols that exploit microwave-assisted synthesis.