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

doi:10.1016/j.apsb.2020.09.002

	Design, synthesis and biological evaluation of pyrazolo[3,4-d]pyridazinone derivatives as covalent FGFR inhibitors
	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
刊名	ACTA PHARMACEUTICA SINICA B
	2021-03-01
卷号	11 期号:3 页码:781-794
关键词	Tyrosine kinase Covalent FGFR inhibitors Virtual screening Pyrazolo[3,4-d] pyridazinone Structure-activity relationships Antitumor efficacy
ISSN号	2211-3835
DOI	10.1016/j.apsb.2020.09.002
通讯作者	Ai, Jing(jai@simm.ac.cn) ; Zheng, Mingyue(myzheng@simm.ac.cn) ; Liu, Hong(hliu@simm.ac.cn)
英文摘要	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.
资助项目	National Natural Science Foundation of China[81620108027] ; National Natural Science Foundation of China[21632008] ; National Natural Science Foundation of China[81773634] ; National Natural Science Foundation of China[81773762] ; National Science & Technology Major Project Key New Drug Creation and Manufacturing Program (China)[2018ZX09711002] ; Major Project of Chinese National Programs for Fundamental Research and Development[2015CB910304] ; Strategic Priority Research Pro-gram of the Chinese Academy of Sciences[XDA12050201] ; Strategic Priority Research Pro-gram of the Chinese Academy of Sciences[XDA12020000] ; Strategic Priority Research Pro-gram of the Chinese Academy of Sciences[XDA12020103] ; Natural Science Foundation of China for Innovation Research Group (China)[81821005] ; Shanghai Municipal Commission of Health and Family Planning (China)[2020CXJQ02]
WOS关键词	SELECTIVE INHIBITOR ; THERAPEUTIC TARGET ; GROWTH ; DISCOVERY ; POTENT ; CANCER ; RESISTANCE ; MUTATIONS ; RECEPTORS ; BINDING
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	INST MATERIA MEDICA, CHINESE ACAD MEDICAL SCIENCES
WOS记录号	WOS:000629336800014
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/295433]
专题	中国科学院上海药物研究所
通讯作者	Ai, Jing; Zheng, Mingyue; Liu, Hong
作者单位	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
推荐引用方式 GB/T 7714	Wu, Xiaowei,Dai, Mengdi,Cui, Rongrong,et al. Design, synthesis and biological evaluation of pyrazolo[3,4-d]pyridazinone derivatives as covalent FGFR inhibitors[J]. ACTA PHARMACEUTICA SINICA B,2021,11(3):781-794.
APA	Wu, Xiaowei.,Dai, Mengdi.,Cui, Rongrong.,Wang, Yulan.,Li, Chunpu.,...&Liu, Hong.(2021).Design, synthesis and biological evaluation of pyrazolo[3,4-d]pyridazinone derivatives as covalent FGFR inhibitors.ACTA PHARMACEUTICA SINICA B,11(3),781-794.
MLA	Wu, Xiaowei,et al."Design, synthesis and biological evaluation of pyrazolo[3,4-d]pyridazinone derivatives as covalent FGFR inhibitors".ACTA PHARMACEUTICA SINICA B 11.3(2021):781-794.