Design and synthesis of selective degraders of EGFR(L858R/T790M) mutant

doi:10.1016/j.ejmech.2020.112199

	Design and synthesis of selective degraders of EGFR(L858R/T790M) mutant
	Zhang, Xin 2; Xu, Fang 2; Tong, Linjiang 1; Zhang, Tao 1; Xie, Hua 1; Lu, Xiaoyun 2; Ren, Xiaomei 2; Ding, Ke 2
刊名	EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
	2020-04-15
卷号	192 页码:14
关键词	Epidermal growth factor receptor (EGFR) Resistance Proteolysis targeting chimera (PROTAC) Protein degradation
ISSN号	0223-5234
DOI	10.1016/j.ejmech.2020.112199
通讯作者	Ren, Xiaomei(ren_xiaomei@jnu.edu.cn) ; Ding, Ke(dingke@jnu.edu.cn)
英文摘要	A series of PROTAC (proteolysis targeting chimera) based selective EGFR(L858R/T790M) (leucine 858 to arginine 858 mutation and threonine 790 to methionine 790) mutant degraders were designed and synthesized. One of the most potent compounds, 14o, effectively and selectively degraded EGFR(L858R/T790M) with an DC50 value of 5.9 nM, while did not show obvious effect on the wild-type protein. Further mechanism investigation revealed that the degradation was mediated by ubiquitin proteasome pathway. Compound 14o could be utilized as an initial lead molecule for development of new EGFR(L858R/T790M) degrader based therapy. (c) 2020 Elsevier Masson SAS. All rights reserved.
资助项目	National Natural Science Foundation of China[21807044] ; National Natural Science Foundation of China[21572230] ; National Natural Science Foundation of China[81425021] ; National Natural Science Foundation of China[81673285] ; National Natural Science Foundation of China[81820108029] ; Guangdong Province[1814050000441] ; Guangdong Province[2014TQ01R341] ; Guangdong Province[2015A030306042] ; Guangdong Province[2015A030312014] ; Guangdong Province[2016A050502041] ; Guangzhou city[201805010007]
WOS关键词	INDUCED PROTEIN-DEGRADATION ; CELL LUNG-CANCER ; EGFR ; INHIBITOR ; RESISTANCE ; DISCOVERY ; AZD9291 ; MUTATIONS ; DERIVATIVES
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
WOS记录号	WOS:000523563100004
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/280825]
专题	中国科学院上海药物研究所
通讯作者	Ren, Xiaomei; Ding, Ke
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, State Key Lab Drug Res, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China 2.Jinan Univ, Int Cooperat Lab Tradit Chinese Med Modernizat &, Guangzhou City Key Lab Precis Chem Drug Dev, Sch Pharm,Minist Educ MOE China, 601 Huangpu Ave West, Guangzhou 510632, Peoples R China
推荐引用方式 GB/T 7714	Zhang, Xin,Xu, Fang,Tong, Linjiang,et al. Design and synthesis of selective degraders of EGFR(L858R/T790M) mutant[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2020,192:14.
APA	Zhang, Xin.,Xu, Fang.,Tong, Linjiang.,Zhang, Tao.,Xie, Hua.,...&Ding, Ke.(2020).Design and synthesis of selective degraders of EGFR(L858R/T790M) mutant.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,192,14.
MLA	Zhang, Xin,et al."Design and synthesis of selective degraders of EGFR(L858R/T790M) mutant".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 192(2020):14.