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

ChemMedChem. 2015 Feb;10(2):296-303. doi: 10.1002/cmdc.201402428. Epub 2014 Dec 2.


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.

Keywords: BRCA2; RAD51; biophysics; homologous recombination; inhibitors; protein-protein interactions.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs
  • BRCA2 Protein / antagonists & inhibitors
  • BRCA2 Protein / metabolism*
  • Binding Sites
  • Drug Design
  • Humans
  • Molecular Dynamics Simulation
  • Protein Binding
  • Protein Structure, Tertiary
  • Pyrococcus furiosus / enzymology
  • Rad51 Recombinase / antagonists & inhibitors
  • Rad51 Recombinase / genetics
  • Rad51 Recombinase / metabolism*
  • Small Molecule Libraries / chemistry*
  • Small Molecule Libraries / metabolism
  • Structure-Activity Relationship
  • Thermodynamics


  • BRCA2 Protein
  • Small Molecule Libraries
  • Rad51 Recombinase