Synthesis of triazolotriazine derivatives as c-Met inhibitors

被引：6
作者：
Guo, Yuting [1 ,3 ]
Peng, Xia [2 ]
Ji, Yinchun [2 ]
Zhang, Yitong [2 ,3 ]
Ding, Jian [2 ,3 ]
Zhan, Zhengsheng [1 ]
Ai, Jing [2 ,3 ]
Duan, Wenhu [1 ,3 ]
机构：
[1] Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, 555 Zu Chong Zhi Rd, Shanghai 201203, Peoples R China
[2] Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, State Key Lab Drug Res, 555 Zu Chong Zhi Rd, Shanghai 201203, Peoples R China
[3] Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China
来源：
MOLECULAR DIVERSITY | 2021年 / 25卷 / 02期
基金：
中国国家自然科学基金;
关键词：
Receptor tyrosine kinase; c-Met; Triazolotriazine; SAR; Cellular potency; GROWTH-FACTOR RECEPTOR; KINASE INHIBITOR; HIGHLY POTENT; DISCOVERY; IDENTIFICATION; PROTOONCOGENE; CABOZANTINIB; METASTASIS; VOLITINIB; PATHWAY;
D O I：
10.1007/s11030-020-10067-5
中图分类号：
Q5 [生物化学]; Q7 [分子生物学];
学科分类号：
071010 ; 081704 ;
摘要：
Receptor tyrosine kinase c-Met is an important antitumor drug target. Triazolotriazine analogues2-10were prepared efficiently and evaluated the enzymatic and cellular c-Met activities. Brief structure-activity relationships of triazolotriazine core and CF2-quinoline part were investigated, leading to the discovery of compound8with nanomolar enzymatic c-Met activity, and subnanomolar MKN45 and EBC-1 cellular potencies. The proposed binding model of 8 and c-Met unraveled that two canonical hydrogen bonds and a pi-pi stacking interaction formed between the inhibitor and the ATP binding site of c-Met kinase domain, which accounted for its potent c-Met activities. [GRAPHICS] .
引用
收藏
页码：839 / 846
页数：8
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