Discovery of thalidomide-based PROTAC small molecules as the highly efficient SHP2 degraders

doi:10.1016/j.ejmech.2021.113341

	Discovery of thalidomide-based PROTAC small molecules as the highly efficient SHP2 degraders
	Yang, Xiangbo 1,4; Wang, Zhijia 2,3; Pei, Yuan 1,4; Song, Ning 2,4,5; Xu, Lei 2; Feng, Bo 2,6; Wang, Hanlin 2,7; Luo, Xiaomin 2,8; Hu, Xiaobei 2; Qiu, Xiaohui 2
刊名	EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
	2021-06-05
卷号	218 页码:14
关键词	SHP2 degradation Proteolysis targeting chimera (PROTAC) Thalidomide-based heterobifunctional molecules E3 ubiquitin ligase CRBN
ISSN号	0223-5234
DOI	10.1016/j.ejmech.2021.113341
通讯作者	Zhou, Yubo(ybzhou@simm.ac.cn) ; Li, Jia(jli@simm.ac.cn) ; Zhou, Bing(zhoubing@simm.ac.cn)
英文摘要	SHP2, a non-receptor tyrosine phosphatase, plays a pivotal role in numerous oncogenic cell-signaling cascades like RAS-ERK, PI3K-AKT and JAK-STAT. On the other hand, proteolysis targeting chimera (PROTAC) has emerged as a promising strategy for the degradation of disease-related protein of interest (POI). SHP2 degradation via the PROTAC strategy will provide an alternative startegy for SHP2-mediated cancer therapy. Herein we described the design, synthesis and evaluation of a series of thalidomide-based heterobifunctional molecules and identified 11(ZB-S-29) as the highly efficient SHP2 degrader with a DC50 of 6.02 nM. Further mechanism investigation illustrated that 11 came into function through targeted SHP2 protein degradation. (c) 2021 Elsevier Masson SAS. All rights reserved.
资助项目	National Natural Science Foundation of China[81973166] ; National Natural Science Foundation of China[21702218] ; National Natural Science Foundation of China[21772068] ; National Natural Science Foundation of China[81773779] ; National Natural Science Foundation of China[81773568] ; National Natural Science Foundation of China[91753207] ; National Science and Technology Major Project of China[2018ZX09711002-008-004] ; National Science and Technology Major Project of China[2018ZX09711002-008-005] ; National Science and Technology Major Project of China[2018ZX09711002-006-001] ; K. C. Wong Education Foundation ; Youth innovation promotion association[2017333]
WOS关键词	E3 UBIQUITIN LIGASE ; POTENT ; PTPN11 ; DEGRADATION ; PHOSPHATASE ; MUTATIONS ; BROMODOMAIN ; PROTEINS ; COMPLEX
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:000646195900003
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/297366]
专题	中国科学院上海药物研究所
通讯作者	Zhou, Yubo; Li, Jia; Zhou, Bing
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, State Key Lab Drug Res, Shanghai 201203, Peoples R China 2.Chinese Acad Sci, Natl Ctr Drug Screening, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China 3.Jiangnan Univ, Sch Pharmaceut Sci, Wuxi 214122, Jiangsu, Peoples R China 4.Univ Chinese Acad Sci, 19 Yuquan Rd, Beijing 100049, Peoples R China 5.ShanghaiTech Univ, 393 Middle Huaxia Rd, Shanghai 201210, Peoples R China 6.Shenyang Pharmaceut Univ, Sch Life Sci & Biopharmaceut, 103 Wenhua Rd, Shenyang, Liaoning, Peoples R China 7.Fudan Univ, Sch Pharm, Shanghai 201203, Peoples R China 8.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210046, Peoples R China 9.Univ Chinese Acad Sci, Sch Pharmaceut Sci & Technol, Hangzhou Inst Adv Study, Hangzhou 310024, Peoples R China
推荐引用方式 GB/T 7714	Yang, Xiangbo,Wang, Zhijia,Pei, Yuan,et al. Discovery of thalidomide-based PROTAC small molecules as the highly efficient SHP2 degraders[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2021,218:14.
APA	Yang, Xiangbo.,Wang, Zhijia.,Pei, Yuan.,Song, Ning.,Xu, Lei.,...&Zhou, Bing.(2021).Discovery of thalidomide-based PROTAC small molecules as the highly efficient SHP2 degraders.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,218,14.
MLA	Yang, Xiangbo,et al."Discovery of thalidomide-based PROTAC small molecules as the highly efficient SHP2 degraders".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 218(2021):14.