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Small-molecule inhibitors that target protein-protein interactions in the RAD51 family of recombinases.


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Type

Article

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Authors

Scott, Duncan E 
Coyne, Anthony G 
Venkitaraman, Ashok 
Blundell, Tom L 

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.

Description

Keywords

BRCA2, RAD51, biophysics, homologous recombination, inhibitors, protein-protein interactions, Amino Acid Motifs, BRCA2 Protein, Binding Sites, Drug Design, Humans, Molecular Dynamics Simulation, Protein Binding, Protein Structure, Tertiary, Pyrococcus furiosus, Rad51 Recombinase, Small Molecule Libraries, Structure-Activity Relationship, Thermodynamics

Journal Title

ChemMedChem

Conference Name

Journal ISSN

1860-7179
1860-7187

Volume Title

10

Publisher

Wiley
Sponsorship
Engineering and Physical Sciences Research Council (EP/K039520/1)
Medical Research Council (G1001521)
Medical Research Council (MC_UU_12022/1)
Medical Research Council (G1001522)
MRC (MC_UU_12022/8)
We thank the Wellcome Trust for funding (Seeding Drug Discovery GR091058/Z/09/Z and Translation Award GR080083/Z/06)