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J Am Chem Soc ; 143(12): 4766-4774, 2021 03 31.
Article in English | MEDLINE | ID: mdl-33733756

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.


Subject(s)
Proto-Oncogene Proteins c-mdm2/antagonists & inhibitors , Small Molecule Libraries/pharmacology , Sulfonamides/pharmacology , Tumor Suppressor Protein p53/antagonists & inhibitors , 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
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