RAD51 is an ATP-dependent recombinase, recruited by BRCA2 to mediate DNA double-strand breaks repair through homologous recombination and represents an attractive cancer drug target. Herein, we applied for the first-time protein-templated dynamic combinatorial chemistry on RAD51 as a hit identification strategy. Upon design of N-acylhydrazone-based dynamic combinatorial libraries, RAD51 showed a clear templating effect, amplifying 19 N-acylhydrazones. Screening against the RAD51-BRCA2 protein-protein interaction via ELISA assay afforded 10 inhibitors in the micromolar range. Further 19F NMR experiments revealed that 7 could bind RAD51 and be displaced by BRC4, suggesting an interaction in the same binding pocket of BRCA2. These results proved not only that ptDCC could be successfully applied on full-length oligomeric RAD51, but also that it could address the need of alternative strategies toward the identification of small-molecule PPI inhibitors.

Bagnolini, G., Balboni, B., Schipani, F., Gioia, D., Veronesi, M., De Franco, F., et al. (2022). Identification of RAD51-BRCA2 Inhibitors Using N-Acylhydrazone-Based Dynamic Combinatorial Chemistry. ACS MEDICINAL CHEMISTRY LETTERS, 13(8), 1262-1269 [10.1021/acsmedchemlett.2c00063].

Identification of RAD51-BRCA2 Inhibitors Using N-Acylhydrazone-Based Dynamic Combinatorial Chemistry

Bagnolini, G.;Balboni, B.;Roberti, M.;Cavalli, A.
2022

Abstract

RAD51 is an ATP-dependent recombinase, recruited by BRCA2 to mediate DNA double-strand breaks repair through homologous recombination and represents an attractive cancer drug target. Herein, we applied for the first-time protein-templated dynamic combinatorial chemistry on RAD51 as a hit identification strategy. Upon design of N-acylhydrazone-based dynamic combinatorial libraries, RAD51 showed a clear templating effect, amplifying 19 N-acylhydrazones. Screening against the RAD51-BRCA2 protein-protein interaction via ELISA assay afforded 10 inhibitors in the micromolar range. Further 19F NMR experiments revealed that 7 could bind RAD51 and be displaced by BRC4, suggesting an interaction in the same binding pocket of BRCA2. These results proved not only that ptDCC could be successfully applied on full-length oligomeric RAD51, but also that it could address the need of alternative strategies toward the identification of small-molecule PPI inhibitors.
2022
Bagnolini, G., Balboni, B., Schipani, F., Gioia, D., Veronesi, M., De Franco, F., et al. (2022). Identification of RAD51-BRCA2 Inhibitors Using N-Acylhydrazone-Based Dynamic Combinatorial Chemistry. ACS MEDICINAL CHEMISTRY LETTERS, 13(8), 1262-1269 [10.1021/acsmedchemlett.2c00063].
Bagnolini, G.; Balboni, B.; Schipani, F.; Gioia, D.; Veronesi, M.; De Franco, F.; Kaya, C.; Jumde, R. P.; Ortega, J. A.; Girotto, S.; Hirsch, A. K. H....espandi
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11585/901007
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