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

页码：839 / 846

页数：8

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