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J Med Chem. 2017 Mar 9;60(5):1876-1891. doi: 10.1021/acs.jmedchem.6b01645. Epub 2017 Feb 14.

Discovery of Potent and Selective Inhibitors for G9a-Like Protein (GLP) Lysine Methyltransferase.

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Department of Pharmacological Sciences and Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai , New York, New York 10029, United States.
Structural Genomics Consortium, University of Toronto , Toronto, Ontario M5G 1L7, Canada.
Princess Margaret Cancer Centre and Department of Medical Biophysics, University of Toronto , Toronto, Ontario M5G 2M9, Canada.
Department of Pharmacology and Toxicology, University of Toronto , Toronto, Ontario M5S 1A8, Canada.


G9a-like protein (GLP) and G9a are highly homologous protein lysine methyltransferases (PKMTs) sharing approximately 80% sequence identity in their catalytic domains. GLP and G9a form a heterodimer complex and catalyze mono- and dimethylation of histone H3 lysine 9 and nonhistone substrates. Although they are closely related, GLP and G9a possess distinct physiological and pathophysiological functions. Thus, GLP or G9a selective small-molecule inhibitors are useful tools to dissect their distinct biological functions. We previously reported potent and selective G9a/GLP dual inhibitors including UNC0638 and UNC0642. Here we report the discovery of potent and selective GLP inhibitors including 4 (MS0124) and 18 (MS012), which are >30-fold and 140-fold selective for GLP over G9a and other methyltransferases, respectively. The cocrystal structures of GLP and G9a in the complex with either 4 or 18 displayed virtually identical binding modes and interactions, highlighting the challenges in structure-based design of selective inhibitors for either enzyme.

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