Ueda, T, Tamura, T, Kawano, M et al. (4 more authors) (2021) Enhanced suppression of a protein-protein interaction in cells using small-molecule covalent inhibitors based on N-acyl-N-alkyl sulfonamide warhead. Journal of the American Chemical Society. ISSN 0002-7863
Abstract
Protein–protein interactions (PPIs) intimately govern various biological processes and disease states and therefore have been identified as attractive therapeutic targets for small-molecule drug discovery. However, the development of highly potent inhibitors for PPIs has proven to be extremely challenging with limited clinical success stories. Herein, we report irreversible inhibitors of the human double minute 2 (HDM2)/p53 PPI, which employ a reactive N-acyl-N-alkyl sulfonamide (NASA) group as a warhead. Mass-based analysis successfully revealed the kinetics of covalent inhibition and the modification sites on HDM2 to be the N-terminal α-amine and Tyr67, both rarely seen in traditional covalent inhibitors. Finally, we demonstrated prolonged p53-pathway activation and more effective induction of the p53-mediated cell death in comparison to a noncovalent inhibitor. This study highlights the potential of the NASA warhead as a versatile electrophile for the covalent inhibition of PPIs and opens new avenues for the rational design of potent covalent PPI inhibitors.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2021 American Chemical Society. This is an author produced version of an article, published in Journal of the American Chemical Society (JACS). Uploaded in accordance with the publisher's self-archiving policy. |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Engineering & Physical Sciences (Leeds) > School of Chemistry (Leeds) > Organic Chemistry (Leeds) |
Depositing User: | Symplectic Publications |
Date Deposited: | 23 Mar 2021 15:09 |
Last Modified: | 18 Mar 2022 01:38 |
Status: | Published online |
Publisher: | American Chemical Society |
Identification Number: | 10.1021/jacs.1c00703 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:171967 |