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.
School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China.
J Med Chem. 2024 Aug 8;67(15):13271-13285. doi: 10.1021/acs.jmedchem.4c01192. Epub 2024 Jul 23.
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 , which induced a dose- and time-dependent G9a degradation without degradation of GLP. exhibited effective antiproliferative activities in a panel of pancreatic cancer cell lines and was able to sensitize KRAS mutant pancreatic cancer cells to KRAS 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.
G9a 最初被鉴定为组蛋白 H3 Lys9（H3K9）甲基转移酶，是人类癌症潜在的有吸引力的治疗靶点。尽管它很重要，但由于其同源蛋白 GLP 与 G9a 的序列约有 80%相同，因此没有可用的选择性 G9a 化学探针。开发对 G9a 具有高选择性而对 GLP 没有选择性的 G9a 化学探针是一个巨大的挑战，但对于理解 G9a 相关生物学具有极高的价值。在此，我们开发了一种首创的选择性 G9a 降解剂，它可诱导剂量和时间依赖性 G9a 降解，而不会降解 GLP。在一系列胰腺癌细胞系中， 表现出有效的抗增殖活性，并能够使 KRAS 突变型胰腺癌细胞对 KRAS 抑制剂 MRTX1133 敏感。这些数据清楚地表明，作为一种适合于理解 G9a 相关生物学的初步化学探针的选择性 G9a 降解剂具有实用性和重要性，是治疗胰腺癌的一种有前途的策略。
