Design, Synthesis, and Pharmacological Evaluation of Novel Multisubstituted Pyridin-3-amine Derivatives as Multitargeted Protein Kinase Inhibitors for the Treatment of Non-Small Cell Lung Cancer

doi:10.1021/acs.jmedchem.7b00076

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	Design, Synthesis, and Pharmacological Evaluation of Novel Multisubstituted Pyridin-3-amine Derivatives as Multitargeted Protein Kinase Inhibitors for the Treatment of Non-Small Cell Lung Cancer
	Zhu, Wei 1,2,3; Chen, Hui 1,3; Wang, Yulan 1,3; Wang, Jiang1,2,3 ; Peng, Xia 1,3; Chen, Xianjie 1,2,3; Gao, Yinglei 1,3; Li, Chunpu 1,2,3; He, Yulong 1,2,3; Ai, Jing1,3
刊名	JOURNAL OF MEDICINAL CHEMISTRY
	2017-07-27
卷号	60 期号:14 页码:6018-6035
ISSN号	0022-2623
DOI	10.1021/acs.jmedchem.7b00076
文献子类	Article
英文摘要	A novel series of pyridin-3-amine derivatives were designed, synthesized, and evaluated as multitargeted protein kinase inhibitors for the treatment of non-small cell lung cancer (NSCLC). Hit 1 was first disclosed by in silico screening against fibroblast growth factor receptors (FGFR), which was subsequently validated by in vitro experiments. The structure activity relationship (SAR) of its analogues was then explored to afford novel FGFR. inhibitors 2a-2p and 3a-3q. Among them, 3m showed potent inhibition against FGFR1, 2, and 3. Interestingly, compound 3m not only inhibited various phosphorylation and downstream signaling across different oncogenic forms in FGFR-overactivated cancer cells but also showed nanomolar level inhibition against several other NSCLC-related oncogene kinases, including RET, EGFR, EGFR/T790M/L8S8R, DDR2, and ALK Finally, in vivo pharmacology evaluations of 3m showed significant antitumor activity (TGI = 66.1%) in NCI-H1581 NSCLC xenografts with a good pharmacokinetic profile.
资助项目	National Natural Science Foundation of China[21632008] ; National Natural Science Foundation of China[81620108027] ; National Natural Science Foundation of China[81473243] ; NSFC-Shandong Joint Fund for Marine Science Research Centers[U1406402] ; Major Project of Chinese National Programs for Fundamental Research and Development[2015CB910304] ; Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12050201]
WOS关键词	RECEPTOR TYROSINE KINASE ; SELECTIVE INHIBITOR ; COMPOUND LIBRARIES ; SOLID TUMORS ; PHASE-II ; POTENT ; DISCOVERY ; GENERATION ; MODELS ; FAMILY
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	AMER CHEMICAL SOC
WOS记录号	WOS:000406727700005
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/272555]
专题	药理学第一研究室中科院受体结构与功能重点实验室新药研究国家重点实验室药物发现与设计中心药物化学研究室
通讯作者	Ai, Jing; Zheng, Mingyue; Liu, Hong
作者单位	1.Chinese Acad Sci, State Key Lab Drug Res, 555 Zu Chong Zhi Rd, Shanghai 201203, Peoples R China; 2.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, 555 Zu Chong Zhi Rd, Shanghai 201203, Peoples R China; 3.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China
推荐引用方式 GB/T 7714	Zhu, Wei,Chen, Hui,Wang, Yulan,et al. Design, Synthesis, and Pharmacological Evaluation of Novel Multisubstituted Pyridin-3-amine Derivatives as Multitargeted Protein Kinase Inhibitors for the Treatment of Non-Small Cell Lung Cancer[J]. JOURNAL OF MEDICINAL CHEMISTRY,2017,60(14):6018-6035.
APA	Zhu, Wei.,Chen, Hui.,Wang, Yulan.,Wang, Jiang.,Peng, Xia.,...&Liu, Hong.(2017).Design, Synthesis, and Pharmacological Evaluation of Novel Multisubstituted Pyridin-3-amine Derivatives as Multitargeted Protein Kinase Inhibitors for the Treatment of Non-Small Cell Lung Cancer.JOURNAL OF MEDICINAL CHEMISTRY,60(14),6018-6035.
MLA	Zhu, Wei,et al."Design, Synthesis, and Pharmacological Evaluation of Novel Multisubstituted Pyridin-3-amine Derivatives as Multitargeted Protein Kinase Inhibitors for the Treatment of Non-Small Cell Lung Cancer".JOURNAL OF MEDICINAL CHEMISTRY 60.14(2017):6018-6035.