Design, synthesis and biological evaluation of potent EGFR kinase inhibitors against 19D/T790M/C797S mutation

doi:10.1016/j.bmcl.2020.127327

	Design, synthesis and biological evaluation of potent EGFR kinase inhibitors against 19D/T790M/C797S mutation
	Su, Zhicheng 1; Yang, Tingyuan 1; Wang, Jie 1; Lai, Mengzhen 2,4; Tong, Linjiang 2; Wumaier, Gulinuer 3; Chen, Zhuo 1; Li, Shengqing 3; Li, Honglin 1; Xie, Hua 2
刊名	BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
	2020-08-15
卷号	30 期号:16 页码:6
关键词	EGFR NSCLC C797S
ISSN号	0960-894X
DOI	10.1016/j.bmcl.2020.127327
通讯作者	Chen, Zhuo(chenzhuo@ecust.edu.cn) ; Xie, Hua(hxie@simm.ac.cn) ; Zhao, Zhenjiang(zhjzhao@ecust.edu.cn)
英文摘要	The efficacy of EGFR inhibitors is frequently affected by acquired resistance. EGFR(19D/T790M/C797S) mutation is one of the primary reasons for the emergence of resistance after treatment with the third-generation EGFR inhibitors such as AZD9291, CO1686 and Olmutinib. To overcome the resistance mutation 19D/T790M/C797S, we designed and prepared a series of indole derivatives with the terminal hydroxyl of alkyl chain to increase extra interaction with the Asp855 in the conservative DFG site. Activity evaluation, structure-activity relationship and docking analysis were also carried out. Among them, compound 12e displayed significant inhibitory activity against EGFR(19D/T790M/C797S) (IC50 = 15.3 nM) and good selectivity over EGFR WT (IC50 > 1000 nM), L858R/T790M (IC50, 156.6 nM) and L858R/T790M/C797S (IC50, 218.3 nM) respectively. Furthermore, 12e exhibited good growth inhibition activity, induced G1 phase cell cycle arrest and apoptosis in BaF3/EGFR(19D/T790M/C797S) cells by suppressing EGFR phosphorylation signaling pathway. In all, our study might provide a novel structural design method and lay the solid foundation for the development of the 4th generation EGFR(19D/T790M/C797S) inhibitors.
资助项目	National Key Research and Development Program[2016YFA0502304] ; National Natural Science Foundation of China[81825020] ; National Science & Technology Major Project Key New Drug Creation and Manufacturing Program, China[2018ZX09711002] ; Special Program for Applied Research on Super Computation of the NSFC-Guangdong Joint Fund (the second phase)[U1501501] ; National Program for Special Supports of Eminent Professionals ; National Program for Support of Top-Notch Young Professionals
WOS关键词	CELL LUNG-CANCER ; ACQUIRED-RESISTANCE ; C797S MUTATION ; MUTANT ; DISCOVERY ; GEFITINIB ; AZD9291
WOS研究方向	Pharmacology & Pharmacy ; Chemistry
语种	英语
出版者	PERGAMON-ELSEVIER SCIENCE LTD
WOS记录号	WOS:000551073500007
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/292187]
专题	中国科学院上海药物研究所
通讯作者	Chen, Zhuo; Xie, Hua; Zhao, Zhenjiang
作者单位	1.East China Univ Sci & Technol, Sch Pharm, Shanghai Key Lab New Drug Design, Shanghai 200237, 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.Fudan Univ, Huashan Hosp, Dept Pulm & Crit Care Med, Shanghai, Peoples R China 4.Fudan Univ, Sch Pharm, Shanghai 201203, Peoples R China
推荐引用方式 GB/T 7714	Su, Zhicheng,Yang, Tingyuan,Wang, Jie,et al. Design, synthesis and biological evaluation of potent EGFR kinase inhibitors against 19D/T790M/C797S mutation[J]. BIOORGANIC & MEDICINAL CHEMISTRY LETTERS,2020,30(16):6.
APA	Su, Zhicheng.,Yang, Tingyuan.,Wang, Jie.,Lai, Mengzhen.,Tong, Linjiang.,...&Zhao, Zhenjiang.(2020).Design, synthesis and biological evaluation of potent EGFR kinase inhibitors against 19D/T790M/C797S mutation.BIOORGANIC & MEDICINAL CHEMISTRY LETTERS,30(16),6.
MLA	Su, Zhicheng,et al."Design, synthesis and biological evaluation of potent EGFR kinase inhibitors against 19D/T790M/C797S mutation".BIOORGANIC & MEDICINAL CHEMISTRY LETTERS 30.16(2020):6.