期刊
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
卷 143, 期 12, 页码 4766-4774出版社
AMER CHEMICAL SOC
DOI: 10.1021/jacs.1c00703
关键词
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资金
- Japan Society for the Promotion of Science (JSPS)
- Japan Science and Technology Agency (JST) ERATO grant [JPMJER1802]
- EPSRC [EP/N013573/1]
- Royal Society Leverhulme Trust Senior Fellowship [SRF/R1/191087]
- [18K14334]
- [19H05764]
- [17H06348]
- EPSRC [EP/N035267/1] Funding Source: UKRI
This study presents irreversible inhibitors of the human double minute 2 (HDM2)/p53 protein-protein interaction, utilizing the NASA warhead group, which showed promising potential for covalent inhibition of PPIs and provides new avenues for the rational design of potent covalent PPI inhibitors.
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 alpha-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.
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