A small-molecule inhibitor of the BRCA2-RAD51 interaction modulates RAD51 assembly and potentiates DNA damage-induced cell death

Cell Chem Biol. 2021 Jun 17;28(6):835-847.e5. doi: 10.1016/j.chembiol.2021.02.006. Epub 2021 Mar 3.


BRCA2 controls RAD51 recombinase during homologous DNA recombination (HDR) through eight evolutionarily conserved BRC repeats, which individually engage RAD51 via the motif Phe-x-x-Ala. Using structure-guided molecular design, templated on a monomeric thermostable chimera between human RAD51 and archaeal RadA, we identify CAM833, a 529 Da orthosteric inhibitor of RAD51:BRC with a Kd of 366 nM. The quinoline of CAM833 occupies a hotspot, the Phe-binding pocket on RAD51 and the methyl of the substituted α-methylbenzyl group occupies the Ala-binding pocket. In cells, CAM833 diminishes formation of damage-induced RAD51 nuclear foci; inhibits RAD51 molecular clustering, suppressing extended RAD51 filament assembly; potentiates cytotoxicity by ionizing radiation, augmenting 4N cell-cycle arrest and apoptotic cell death and works with poly-ADP ribose polymerase (PARP)1 inhibitors to suppress growth in BRCA2-wildtype cells. Thus, chemical inhibition of the protein-protein interaction between BRCA2 and RAD51 disrupts HDR and potentiates DNA damage-induced cell death, with implications for cancer therapy.

Keywords: BRCA2; DNA repair; RAD51; RAD51 inhibitor; cancer therapy; homologous recombination; protein-protein interaction inhibition; radiosensitizer; structure-guided drug discovery.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • BRCA2 Protein / antagonists & inhibitors*
  • BRCA2 Protein / chemistry
  • BRCA2 Protein / metabolism
  • Cell Death / drug effects
  • Crystallography, X-Ray
  • DNA Damage
  • Humans
  • Models, Molecular
  • Molecular Conformation
  • Protein Binding / drug effects
  • Rad51 Recombinase / antagonists & inhibitors*
  • Rad51 Recombinase / chemistry
  • Rad51 Recombinase / metabolism
  • Small Molecule Libraries / chemical synthesis
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology*
  • Tumor Cells, Cultured


  • BRCA2 Protein
  • BRCA2 protein, human
  • Small Molecule Libraries
  • Rad51 Recombinase