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

Scott, D. E.; Francis-Newton, N. J.; Marsh, M. E.; Coyne, A. G.; Fischer, G.; Moschetti, T.; Bayly, A. R.; Sharpe, T. D.; Haas, K.; Barber, L.; Valenzano, C.; Srinivasan, R.; Huggins, D. J.; Ehebauer, M.; Esposito, A.; Pellegrini, L.; Perrior, T.; McKenzie, G.; Blundell, T. L.; Hyvonen, M.; Skidmore, J.; Venkitaraman, A. R.; Abell, C.

doi:10.1101/2020.07.15.200709

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bioRxiv · 10.1101/2020.07.15.200709

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

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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 -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 ionising 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.

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Scott, D. E., Francis-Newton, N. J., Marsh, M. E., Coyne, A. G., Fischer, G., Moschetti, T., Bayly, A. R., Sharpe, T. D., Haas, K., Barber, L., Valenzano, C., Srinivasan, R., Huggins, D. J., Ehebauer, M., Esposito, A., Pellegrini, L., Perrior, T., McKenzie, G., Blundell, T. L., Hyvonen, M., Skidmore, J., Venkitaraman, A. R., Abell, C.. 2020-07-15. A small-molecule inhibitor of the BRCA2-RAD51 interaction modulates RAD51 assembly and potentiates DNA damage-induced cell death. https://doi.org/10.1101/2020.07.15.200709

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