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Enhanced Suppression of a Protein-Protein Interaction in Cells Using Small-Molecule Covalent Inhibitors Based on an N -Acyl- N -alkyl Sulfonamide Warhead.
- Source :
-
Journal of the American Chemical Society [J Am Chem Soc] 2021 Mar 31; Vol. 143 (12), pp. 4766-4774. Date of Electronic Publication: 2021 Mar 18. - Publication Year :
- 2021
-
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.
- Subjects :
- Cell Line, Tumor
Drug Design
Humans
Molecular Structure
Protein Binding drug effects
Proto-Oncogene Proteins c-mdm2 chemistry
Small Molecule Libraries chemical synthesis
Small Molecule Libraries chemistry
Sulfonamides chemical synthesis
Sulfonamides chemistry
Tumor Suppressor Protein p53 chemistry
Proto-Oncogene Proteins c-mdm2 antagonists & inhibitors
Small Molecule Libraries pharmacology
Sulfonamides pharmacology
Tumor Suppressor Protein p53 antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1520-5126
- Volume :
- 143
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- Journal of the American Chemical Society
- Publication Type :
- Academic Journal
- Accession number :
- 33733756
- Full Text :
- https://doi.org/10.1021/jacs.1c00703