A small-molecule inhibitor of the BRCA2-RAD51 interaction modulates RAD51 assembly and potentiates DNA damage-induced cell death
Duncan E. Scott, Nicola J. Francis-Newton, M. Marsh, Anthony G. Coyne, Gerhard W. Fischer, Tommaso Moschetti, Andrew R. Bayly, Timothy Sharpe, Kalina T. Haas, Lorraine Barber, Chiara R. Valenzano, Rajavel Srinivasan, David J. Huggins, Mi-Young Lee, Amy Emery, B. Hardwick, M.T. Ehebauer, Claudio Dagostin, Alessandro Esposito, Luca Pellegrini, Trevor R. Perrior, Grahame J. McKenzie, Tom L. Blundell, Marko Hyvönen, John Skidmore, Ashok R. Venkitaraman, Chris Abell
Abstract
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.