Design and synthesis of RAD51-BRCA2 protein-protein interaction disruptors to trigger synthetic lethality with Olaparib in pancreatic cancer cells

Synthetic lethality (SL) is a phenotypic condition in which cells do not survive due to the combination of two genetic perturbations that, taken individually, do not induce cell death. A successful application is the use of PARP inhibitors in cancer patients with BRCA2 mutations. One of the key mechanisms of BRCA2 is to recruit the Rad51 to the site of double-strand breaks where it performs homologous recombination repair.1 Our research project focuses on the development of Rad51-BRCA2 protein-protein interaction (PPI) disruptors that mimic the BRCA2 mutation to trigger fully small organic molecule SL in combination with Olaparib in BRCA2-functional pancreatic cancer cells.2 Due to the low in vivo bioavailability of the previous lead compound,3 a quinoline-structured Rad51-BRCA2 disruptor (ARN22142, Scheme 1) has been identified through a virtual screening campaign on a specific zone of PPI. To discover more effective compounds and depict general structure-activity relationship studies, the chemical space around ARN22142 has been explored by optimizing a general synthetic strategy and building a library of quinolinic analogues modified in two moieties of interest (red and blue residues, Scheme 1). Among the synthetized compounds, derivative ARN26912 has showed synergism on the antiproliferative efficacy with Olaparib in BRCA2-proficient pancreatic cancer cell lines. This supports the idea that small organic molecules can mimic genetic mutations. Further in vitro biological studies will be done with this promising compound.