5-Methoxyquinoline Derivatives as a New Class of EZH2 Inhibitors
Pu Xiang,
Hui Jie,
Yang Zhou,
Bo Yang,
Hui-Juan Wang,
Jing Hu,
Jian Hu,
Sheng-Yong Yang,
Ying-Lan Zhao
Affiliations
Pu Xiang
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China
Hui Jie
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China
Yang Zhou
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China
Bo Yang
West China School of Pharmacy, Sichuan University, Chengdu 610041, China
Hui-Juan Wang
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China
Jing Hu
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China
Jian Hu
The Second Division of Hepatobiliary Surgery, Center of PLA, Center of General Surgery of PLA, General Hospital of Chengdu Military Region, Chengdu 610083, China
Sheng-Yong Yang
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China
Ying-Lan Zhao
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China
A series of quinoline derivatives was synthesized and biologically evaluated as Enhancer of Zeste Homologue 2 (EZH2) inhibitors. Structure-activity relationship (SAR) studies led to the discovery of 5-methoxy-2-(4-methyl-1,4-diazepan-1-yl)-N-(1-methylpiperidin-4-yl)quinolin-4-amine (5k), which displayed an IC50 value of 1.2 μM against EZH2, decreased global H3K27me3 level in cells and also showed good anti-viability activities against two tumor cell lines. Due to the low molecular weight and the fact that no quinoline derivative has been reported as an EZH2 inhibitor, this compound could serve as a lead compound for further optimization.