2. Academic Validation
  3. Structure-Based Design and Characterization of the Highly Potent and Selective Covalent Inhibitors Targeting the Lysine Methyltransferases G9a/GLP

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

  • J Med Chem. 2023 Jun 22;66(12):8086-8102. doi: 10.1021/acs.jmedchem.3c00411.
Zongbo Feng 1 2,  Chunju Yang 1,  Yi Zhang 1,  Huaxuan Li 1 3,  Wei Fang 1,  Junhua Wang 4,  Yichu Nie 5,  Chang-Yun Wang 3,  Zhiqing Liu 3,  Zhimin Jiang 2,  Junjian Wang 1,  Yuanxiang Wang 1
Affiliations

Affiliations

  • 1 Balance-Based Drug Discovery Laboratory, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China.
  • 2 School of Pharmacy, Guilin Medical University, Zhiyuan Road, Lingui District, Guilin 541199, China.
  • 3 School of Medicine and Pharmacy, Institute of Evolution & Marine Biodiversity, College of Food Science and Engineering, Ocean University of China, Qingdao 266003, China.
  • 4 The Department of Biliary-Pancreatic Surgery, The First People's Hospital of Foshan, Foshan 528000, China.
  • 5 Clinical Research Institute, The First People's Hospital of Foshan, Foshan 528000, China.
PMID: 37268593 DOI: 10.1021/acs.jmedchem.3c00411
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.

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