Related Experiment Video
Updated: Jul 28, 2025

Specificity Analysis of Protein Lysine Methyltransferases Using SPOT Peptide Arrays
Published on: November 29, 2014
Structure-Based Design and Characterization of the Highly Potent and Selective Covalent Inhibitors Targeting the
Zongbo Feng1,2, Chunju Yang1, Yi Zhang1
1Balance-Based Drug Discovery Laboratory, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China.
Abstract:
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.
Related Concept Videos
Covalently Linked Protein Regulators
These groups modify specific amino acids in a protein....
Ligand Binding and Linkage

