Design, synthesis and biological evaluation of pyrazolo[3,4-d]pyridazinone derivatives as covalent FGFR inhibitors

被引：19

作者：

Wu, Xiaowei ^{[1
]}

Dai, Mengdi ^{[2
,3
]}

Cui, Rongrong ^{[4
]}

Wang, Yulan ^{[1
]}

Li, Chunpu ^{[1
]}

Peng, Xia ^{[2
]}

Zhao, Jihui ^{[1
,3
]}

Wang, Bao ^{[1
]}

Dai, Yang ^{[2
]}

Feng, Dan ^{[1
]}

Yang, Tianbiao ^{[1
]}

Jiang, Hualiang ^{[1
,4
]}

Geng, Meiyu ^{[2
]}

Ai, Jing ^{[2
,3
]}

Zheng, Mingyue ^{[1
,3
,4
]}

Liu, Hong ^{[1
]}

机构：

[1] Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China

[2] Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, State Key Lab Drug Res, Shanghai 201203, Peoples R China

[3] Univ Chinese Acad Sci, Beijing 100049, Peoples R China

[4] Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China

来源：

ACTA PHARMACEUTICA SINICA B | 2021年 / 11卷 / 03期

基金：

中国国家自然科学基金;

关键词：

Tyrosine kinase; Covalent FGFR inhibitors; Virtual screening; Pyrazolo[3,4-d] pyridazinone; Structure-activity relationships; Antitumor efficacy; SELECTIVE INHIBITOR; THERAPEUTIC TARGET; GROWTH; DISCOVERY; POTENT; CANCER; RESISTANCE; MUTATIONS; RECEPTORS; BINDING;

D O I：

10.1016/j.apsb.2020.09.002

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

Fibroblast growth factor receptors (FGFRs) have emerged as promising targets for anticancer therapy. In this study, we synthesized and evaluated the biological activity of 66 pyrazolo[3,4-d]pyridazinone derivatives. Kinase inhibition, cell proliferation, and whole blood stability assays were used to evaluate their activity on FGFR, allowing us to explore structure-activity relationships and thus to gain understanding of the structural requirements to modulate covalent inhibitors' selectivity and reactivity. Among them, compound 10h exhibited potent enzymatic activity against FGFR and remarkably inhibited proliferation of various cancer cells associated with FGFR dysregulation, and suppressed FGFR signaling pathway in cancer cells by the immunoblot analysis. Moreover, 10h displayed highly potent antitumor efficacy (TGI = 91.6%, at a dose of 50 mg/kg) in the FGFR1-amplified NCI-H1581 xenograft model. (C) 2021 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.

引用

页码：781 / 794

页数：14

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