Discovery of a small-molecule inhibitor that traps Polθ on DNA and synergizes with PARP inhibitors

Discovery of a small-molecule inhibitor that traps Polθ on DNA and synergizes with PARP inhibitors

Abstract The DNA damage response (DDR) protein DNA Polymerase θ (Polθ) is synthetic lethal with homologous recombination (HR) factors and is therefore a promising drug target in BRCA1/2 mutant cancers. We discover an allosteric Polθ inhibitor (Polθi) class with 4–6 nM IC50 that selectively kills HR-...

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Bibliographic Details
Main Authors: William Fried, Mrityunjay Tyagi, Leonid Minakhin, Gurushankar Chandramouly, Taylor Tredinnick, Mercy Ramanjulu, William Auerbacher, Marissa Calbert, Timur Rusanov, Trung Hoang, Nikita Borisonnik, Robert Betsch, John J. Krais, Yifan Wang, Umeshkumar M. Vekariya, John Gordon, George Morton, Tatiana Kent, Tomasz Skorski, Neil Johnson, Wayne Childers, Xiaojiang S. Chen, Richard T. Pomerantz
Format: Article
Language:English
Published: Nature Portfolio 2024-04-01
Series:Nature Communications
Online Access:https://doi.org/10.1038/s41467-024-46593-1

Internet

https://doi.org/10.1038/s41467-024-46593-1

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