Structure-Based Design and Characterization of the Highly Potent and Selective Covalent Inhibitors Targeting the Lysine Methyltransferases G9a/GLP

Proteinlysine methyltransferases G9a and GLP, which catalyze mono-and di-methylation of histone H3K9 and nonhistone proteins, play importantroles in diverse cellular processes. Overexpression or dysregulationof G9a and GLP has been identified in various types of cancer. Here,we report the discovery of a highly potent and selective covalentinhibitor 27 of G9a/GLP via the structure-based drugdesign approach following structure-activity relationship explorationand cellular potency optimization. Mass spectrometry assays and washoutexperiments confirmed its covalent inhibition mechanism. Compound 27 displayed improved potency in inhibiting the proliferationand colony formation of PANC-1 and MDA-MB-231 cell lines and exhibitedenhanced potency in reducing the levels of H3K9me2 in cells comparedto noncovalent inhibitor 26. In vivo, 27 showed significant antitumor efficacy in the PANC-1xenograft model with good safety. These results clearly indicate that 27 is a highly potent and selective covalent inhibitor ofG9a/GLP.

Automated summary

Protein lysine methyltransferases G9a and GLP are important in cellular processes. A covalent inhibitor, compound 27, has been discovered to effectively inhibit cell proliferation and reduce H3K9me2 levels. It also shows significant antitumor efficacy in vivo.