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Discovery and Characterization of a Novel Series of Chloropyrimidines as Covalent Inhibitors of the Kinase MSK1.

ABSTRACT: We describe the identification and characterization of a series of covalent inhibitors of the C-terminal kinase domain (CTKD) of MSK1. The initial hit was identified via a high-throughput screening and represents a rare example of a covalent inhibitor which acts via an S_NAr reaction of a 2,5-dichloropyrimidine with a cysteine residue (Cys440). The covalent mechanism of action was supported by in vitro biochemical experiments and was confirmed by mass spectrometry. Ultimately, the displacement of the 2-chloro moiety was confirmed by crystallization of an inhibitor with the CTKD. We also disclose the crystal structures of three compounds from this series bound to the CTKD of MSK1, in addition to the crystal structures of two unrelated RSK2 covalent inhibitors bound to the CTKD of MSK1.

SUBMITTER: Hall A

PROVIDER: S-EPMC9290008 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

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Discovery and Characterization of a Novel Series of Chloropyrimidines as Covalent Inhibitors of the Kinase MSK1.

Hall Adrian A Abendroth Jan J Bolejack Madison J MJ Ceska Tom T Dell'Aiera Sylvie S Ellis Victoria V Fox David D François Cyril C Muruthi Muigai M MM Prével Camille C Poullennec Karine K Romanov Sergei S Valade Anne A Vanbellinghen Alain A Yano Jason J Geraerts Martine M

ACS medicinal chemistry letters 20220625 7

We describe the identification and characterization of a series of covalent inhibitors of the C-terminal kinase domain (CTKD) of MSK1. The initial hit was identified via a high-throughput screening and represents a rare example of a covalent inhibitor which acts via an S<sub>N</sub>Ar reaction of a 2,5-dichloropyrimidine with a cysteine residue (Cys440). The covalent mechanism of action was supported by <i>in vitro</i> biochemical experiments and was confirmed by mass spectrometry. Ultimately, t ...[more]

PMID: 35859861

Dataset Information

Discovery and Characterization of a Novel Series of Chloropyrimidines as Covalent Inhibitors of the Kinase MSK1.

Publications

Discovery and Characterization of a Novel Series of Chloropyrimidines as Covalent Inhibitors of the Kinase MSK1.

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