1. New RAD51 Inhibitors to Target Homologous Recombination in Human Cells.
- Author
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Shkundina IS, Gall AA, Dick A, Cocklin S, and Mazin AV
- Subjects
- Antineoplastic Agents chemistry, Binding Sites, Cell Line, Tumor, Cell Proliferation drug effects, Drug Synergism, Enzyme Inhibitors chemistry, Humans, Molecular Docking Simulation, Phthalazines pharmacology, Piperazines pharmacology, Protein Binding, Quinazolinones chemistry, Rad51 Recombinase chemistry, Rad51 Recombinase metabolism, Antineoplastic Agents pharmacology, Enzyme Inhibitors pharmacology, Homologous Recombination drug effects, Quinazolinones pharmacology, Rad51 Recombinase antagonists & inhibitors
- Abstract
Targeting DNA repair proteins with small-molecule inhibitors became a proven anti-cancer strategy. Previously, we identified an inhibitor of a major protein of homologous recombination (HR) RAD51, named B02. B02 inhibited HR in human cells and sensitized them to chemotherapeutic drugs in vitro and in vivo . Here, using a medicinal chemistry approach, we aimed to improve the potency of B02. We identified the B02 analog, B02-isomer, which inhibits HR in human cells with significantly higher efficiency. We also show that B02-iso sensitizes triple-negative breast cancer MDA-MB-231 cells to the PARP inhibitor (PARPi) olaparib.
- Published
- 2021
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