Small‐Molecule Inhibitors That Target Protein–Protein Interactions in the RAD51 Family of Recombinases

• DOI: 10.1002/cmdc.201402428
• Publication Date: 2014-12-03T00:59:46Z
• Authors: Duncan E. Scott; Anthony G. Coyne; Ashok Venkitaraman; Tom L. Blundell; Chris Abell; Marko Hyvönen
• Keywords: Tetrapeptide; Chemical Biology

Abstract The development of small molecules that inhibit protein–protein interactions continues to be a challenge in chemical biology and drug discovery. Herein we report the indole‐based fragments bind shallow surface pocket humanised surrogate RAD51. RAD51 is an ATP‐dependent recombinase plays key role repair double‐strand DNA breaks. It both self‐associates, forming filament structures with DNA, interacts BRCA2 protein through common “FxxA” tetrapeptide motif. We elaborated previously identified fragment hits target FxxA motif site developed small‐molecule inhibitors are approximately 500‐fold more potent than initial fragments. lead compounds were shown compete BRCA2‐derived Ac‐FHTA‐NH 2 peptide self‐association RAD51, but they had no effect on ATP binding. This study first reported elaboration small‐molecular‐weight against this challenging target.