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Discovery of the First-in-Class G9a/GLP Covalent Inhibitors.

ABSTRACT: The highly homologous protein lysine methyltransferases G9a and GLP, which catalyze mono- and dimethylation of histone H3 lysine 9 (H3K9), have been implicated in various human diseases. To investigate functions of G9a and GLP in human diseases, we and others reported several noncovalent reversible small-molecule inhibitors of G9a and GLP. Here, we report the discovery of the first-in-class G9a/GLP covalent irreversible inhibitors, 1 and 8 (MS8511), by targeting a cysteine residue at the substrate binding site. We characterized these covalent inhibitors in enzymatic, mass spectrometry based and cellular assays and using X-ray crystallography. Compared to the noncovalent G9a/GLP inhibitor UNC0642, covalent inhibitor 8 displayed improved potency in enzymatic and cellular assays. Interestingly, compound 8 also displayed potential kinetic preference for covalently modifying G9a over GLP. Collectively, compound 8 could be a useful chemical tool for studying the functional roles of G9a and GLP by covalently modifying and inhibiting these methyltransferases.

SUBMITTER: Park KS 

PROVIDER: S-EPMC9482816 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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Discovery of the First-in-Class G9a/GLP Covalent Inhibitors.

Park Kwang-Su KS   Xiong Yan Y   Yim Hyerin H   Velez Julia J   Babault Nicolas N   Kumar Prashasti P   Liu Jing J   Jin Jian J  

Journal of medicinal chemistry 20220628 15

The highly homologous protein lysine methyltransferases G9a and GLP, which catalyze mono- and dimethylation of histone H3 lysine 9 (H3K9), have been implicated in various human diseases. To investigate functions of G9a and GLP in human diseases, we and others reported several noncovalent reversible small-molecule inhibitors of G9a and GLP. Here, we report the discovery of the first-in-class G9a/GLP covalent irreversible inhibitors, <b>1</b> and <b>8</b> (MS8511), by targeting a cysteine residue  ...[more]

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