Small‐Molecule Inhibitors That Target Protein–Protein Interactions in the RAD51 Family of Recombinases |
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Authors: | Dr. Duncan E. Scott Dr. Anthony G. Coyne Prof. Ashok Venkitaraman Prof. Tom L. Blundell Prof. Chris Abell Dr. Marko Hyvönen |
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Affiliation: | 1. Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2?1EW (UK);2. Medical Research Council Cancer Unit, University of Cambridge, Hills Road, Cambridge CB2?0XZ (UK);3. Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Old Addenbrooke's Site, Cambridge, CB2?1GA (UK) |
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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 development of indole‐based fragments that bind in a shallow surface pocket of a humanised surrogate of RAD51. RAD51 is an ATP‐dependent recombinase that plays a key role in the repair of double‐strand DNA breaks. It both self‐associates, forming filament structures with DNA, and interacts with the BRCA2 protein through a common “FxxA” tetrapeptide motif. We elaborated previously identified fragment hits that target the FxxA motif site and developed small‐molecule inhibitors that are approximately 500‐fold more potent than the initial fragments. The lead compounds were shown to compete with the BRCA2‐derived Ac‐FHTA‐NH2 peptide and the self‐association peptide of RAD51, but they had no effect on ATP binding. This study is the first reported elaboration of small‐molecular‐weight fragments against this challenging target. |
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Keywords: | biophysics BRCA2 homologous recombination inhibitors protein– protein interactions RAD51 |
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