2. Academic Validation
  3. A small-molecule inhibitor of the BRCA2-RAD51 interaction modulates RAD51 assembly and potentiates DNA damage-induced cell death

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.
Duncan E Scott 1,  Nicola J Francis-Newton 2,  May E Marsh 3,  Anthony G Coyne 1,  Gerhard Fischer 3,  Tommaso Moschetti 3,  Andrew R Bayly 1,  Timothy D Sharpe 3,  Kalina T Haas 2,  Lorraine Barber 2,  Chiara R Valenzano 1,  Rajavel Srinivasan 1,  David J Huggins 4,  Miyoung Lee 2,  Amy Emery 2,  Bryn Hardwick 2,  Matthias Ehebauer 3,  Claudio Dagostin 1,  Alessandro Esposito 2,  Luca Pellegrini 3,  Trevor Perrior 5,  Grahame McKenzie 2,  Tom L Blundell 3,  Marko Hyvönen 6,  John Skidmore 7,  Ashok R Venkitaraman 8,  Chris Abell 1
Affiliations

Affiliations

  • 1 Yusuf Hamied Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.
  • 2 Medical Research Council Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Hills Road, Cambridge CB2 0XZ, UK.
  • 3 Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, UK.
  • 4 Yusuf Hamied Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK; Medical Research Council Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Hills Road, Cambridge CB2 0XZ, UK.
  • 5 Excellium Consulting, Brook Farm Barn, Lackford, Bury St Edmunds IP28 6HL, UK.
  • 6 Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, UK. Electronic address: [email protected].
  • 7 Yusuf Hamied Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK. Electronic address: [email protected].
  • 8 Medical Research Council Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Hills Road, Cambridge CB2 0XZ, UK. Electronic address: [email protected].
PMID: 33662256 DOI: 10.1016/j.chembiol.2021.02.006
Abstract

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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-150147
    99.79%, BRCA2-RAD51 Interaction Inhibitor