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Publication Abstract from PubMed

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.

Discovery of the First-in-Class G9a/GLP Covalent Inhibitors.,Park KS, Xiong Y, Yim H, Velez J, Babault N, Kumar P, Liu J, Jin J J Med Chem. 2022 Aug 11;65(15):10506-10522. doi: 10.1021/acs.jmedchem.2c00652. , Epub 2022 Jun 28. PMID:35763668^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.