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

作者：Kwang‐Su Park, Yan Xiong, Hyerin Yim, Julia Velez, Nicolas Babault, Prashasti Kumar, Jing Liu, Jian Jin · 发表于：Journal of Medicinal Chemistry · 年份：2022 · DOI：10.1021/acs.jmedchem.2c00652 · 被引用次数：46 · 研究领域：Epigenetics and DNA Methylation、Cancer-related gene regulation、HIV Research and Treatment

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.