5-Methoxyquinoline Derivatives as a New Class of EZH2 Inhibitors.
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.
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China.
Pu
P
Xiang
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China.
Hui
H
Jie
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China.
Yang
Y
Zhou
West China School of Pharmacy, Sichuan University, Chengdu 610041, China.
Bo
B
Yang
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China.
Hui-Juan
HJ
Wang
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China.
Jing
J
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.
Jian
J
Hu
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China.
Sheng-Yong
SY
Yang
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China. zhaoyinglan@scu.edu.cn.
Ying-Lan
YL
Zhao
D000634:Aminoquinolines / Q000138:chemical synthesis / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D001381:Azepines / Q000138:chemical synthesis / Q000494:pharmacology*; D045744:Cell Line, Tumor; D019175:DNA Methylation / Q000235:genetics; D000071221:Enhancer of Zeste Homolog 2 Protein; D006657:Histones / Q000235:genetics; D006801:Humans; D009369:Neoplasms / Q000473:pathology; D063151:Polycomb Repressive Complex 2 / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
C000606132:5-methoxy-2-(4-methyl-1,4-diazepan-1-yl)-N-(1-methylpiperidin-4-yl)quinolin-4-amine; D000634:Aminoquinolines; D000970:Antineoplastic Agents; D001381:Azepines; D006657:Histones; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2