title: Small-molecule inhibitors that target protein-protein interactions in the RAD51 family of recombinases.
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.
authors.affiliation: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW (UK).
authors.forename: Duncan E
authors.initials: DE
authors.lastname: Scott
authors.forename: Anthony G
authors.initials: AG
authors.lastname: Coyne
authors.forename: Ashok
authors.initials: A
authors.lastname: Venkitaraman
authors.forename: Tom L
authors.initials: TL
authors.lastname: Blundell
authors.forename: Chris
authors.initials: C
authors.lastname: Abell
authors.forename: Marko
authors.initials: M
authors.lastname: Hyvönen
mesh_terms: D020816:Amino Acid Motifs; D024682:BRCA2 Protein / Q000037:antagonists & inhibitors / Q000378:metabolism*; D001665:Binding Sites; D015195:Drug Design; D006801:Humans; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D020027:Pyrococcus furiosus / Q000201:enzymology; D051135:Rad51 Recombinase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013816:Thermodynamics
chemical_list: D024682:BRCA2 Protein; D054852:Small Molecule Libraries; D051135:Rad51 Recombinase
keywords: BRCA2; RAD51; biophysics; homologous recombination; inhibitors; protein-protein interactions