2. Academic Validation
  3. Discovery of Potent and Selective G9a Degraders for the Treatment of Pancreatic Cancer

Discovery of Potent and Selective G9a Degraders for the Treatment of Pancreatic Cancer

  • J Med Chem. 2024 Aug 8;67(15):13271-13285. doi: 10.1021/acs.jmedchem.4c01192.
Yunkai Shi 1 2 3,  Qianqian Shen 4,  Ruikai Long 2 3,  Yiwen Mao 2 3,  Shuaihang Tong 2 3,  Yaxi Yang 1 2 5 3,  Jing Gao 6 3,  Hu Zhou 6 3,  Yi Chen 4 5 3,  Bing Zhou 1 2 5 3
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China.
  • 2 School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China.
  • 3 University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing 100049, China.
  • 4 Division of Antitumor Pharmacology, State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 5 Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong 264117, China.
  • 6 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China.
PMID: 39041067 DOI: 10.1021/acs.jmedchem.4c01192
Abstract

G9a, which was initially identified as a histone H3 Lys9 (H3K9) methyltransferase, is potentially an attractive therapeutic target for human cancers. Despite its importance, there is no available selective G9a chemical probe because its homologous protein GLP shares approximately 80% of its sequence with G9a. The development of G9a chemical probes with high selectivity for G9a over GLP is a big challenge but is extremely valuable for understanding G9a-related biology. Herein, we developed a first-in-class selective G9a degrader G9D-4, which induced a dose- and time-dependent G9a degradation without degradation of GLP. G9D-4 exhibited effective antiproliferative activities in a panel of pancreatic Cancer cell lines and was able to sensitize KRASG12D mutant pancreatic Cancer cells to KRASG12D inhibitor MRTX1133. These data clearly demonstrated the practicality and importance of a selective G9a degrader as a preliminary chemical probe suitable for understanding G9a-related biology and a promising strategy for the treatment of pancreatic Cancer.

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