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

Protein lysine methyltransferases G9a and GLP, which catalyze mono- and di-methylation of histone H3K9 and nonhistone proteins, play important roles in diverse cellular processes. Overexpression or dysregulation of G9a and GLP has been identified in various types of cancer. Here, we report the disco...

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Published inJournal of medicinal chemistry Vol. 66; no. 12; pp. 8086 - 8102
Main Authors Feng, Zongbo, Yang, Chunju, Zhang, Yi, Li, Huaxuan, Fang, Wei, Wang, Junhua, Nie, Yichu, Wang, Chang-Yun, Liu, Zhiqing, Jiang, Zhimin, Wang, Junjian, Wang, Yuanxiang
Format Journal Article
LanguageEnglish
Published WASHINGTON American Chemical Society 22.06.2023
Amer Chemical Soc
Subjects
Chemistry, Medicinal
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - pharmacology
Enzyme Inhibitors - therapeutic use
Histone-Lysine N-Methyltransferase
Histones - metabolism
Humans
Life Sciences & Biomedicine
Lysine
Pharmacology & Pharmacy
Science & Technology
Structure-Activity Relationship
METHYLATION
BEHAVIOR
DISEASE
CHEMICAL PROBE
SINEFUNGIN
DYNAMICS
G9A INHIBITORS
ESTABLISHMENT
COGNITION
DISCOVERY
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Summary:Protein lysine methyltransferases G9a and GLP, which catalyze mono- and di-methylation of histone H3K9 and nonhistone proteins, play important roles in diverse cellular processes. Overexpression or dysregulation of G9a and GLP has been identified in various types of cancer. Here, we report the discovery of a highly potent and selective covalent inhibitor 27 of G9a/GLP via the structure-based drug design approach following structure–activity relationship exploration and cellular potency optimization. Mass spectrometry assays and washout experiments confirmed its covalent inhibition mechanism. Compound 27 displayed improved potency in inhibiting the proliferation and colony formation of PANC-1 and MDA-MB-231 cell lines and exhibited enhanced potency in reducing the levels of H3K9me2 in cells compared to noncovalent inhibitor 26. In vivo, 27 showed significant antitumor efficacy in the PANC-1 xenograft model with good safety. These results clearly indicate that 27 is a highly potent and selective covalent inhibitor of G9a/GLP.
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ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.3c00411