Design and synthesis of BRCA2-RAD51 disruptors to induce synthetic lethality in anticancer therapy

Synthetic lethality is the lethal phenotype arising from a combination of two gene mutations, which do not affect cell viability when they occur individually. In principle, targeting the synthetic lethal partner of an altered gene in cancer should selectively kill cancer cells while sparing normal cells1. One straightforward application of synthetic lethality in anticancer drug development is the use of Olaparib, the first approved poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitor in BRCA2-defective oncology patients1,2. Based on this assumptions, our group exploited the possibility to achieve a fully small molecules induced synthetic lethality by combining Olaparib with disruptors of the interaction of BRCA2 to its partner protein Rad51 (Figure 1a).To identify disruptors of this protein-protein interaction (Rad51 BRCA2), a virtual screening protocol was performed followed by a preliminary structure-activity relationship (SAR) studies. ARN19793 was identified as the best candidate in terms of chemical tractability and biological activity as it can increase the response to Olaparib in cells expressing a functional Rad51-BRCA2 signaling pathway1. In this context during the first year of my PhD work I will explore the chemical space around ARN19793 by synthesizing a large library of triazoles analogues to provide robust SAR and confirm the druggability of the Rad51-BRCA2 interaction. In particular, I will investigate different lengths of the phenyl alkyl chain also including eteroatoms, several substituents on the benzothiazolinone ring and different dimensions of cycloalkane (Figure 1b). Both conventional chemical procedures and robotized parallel synthesis approaches will be used. To promote sustainable chemistry, I will privilege protocols that exploit microwave-assisted synthesis and/or ionic liquid as reaction media.