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Design, synthesis, and biological evaluation of Wee1 kinase degraders

文献类型：期刊论文

作者Zhu, Shulei5; Liu, Jieyu3,4; Xiao, Donghuai5; Wang, Peipei1,3,4; Ma, Jingkun3,4; Hu, Xiaobei2,3,4; Fu, Jingfeng3,4; Zhou, Yubo1,2,3,4; Li, Jia1,2,3,4; Lu, Wei5
刊名EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
出版日期2022-12-05
卷号243页码:21
ISSN号0223-5234
关键词CRBN Wee1 PROTAC Degradation
DOI10.1016/j.ejmech.2022.114786
通讯作者Zhou, Yubo(ybzhou@simm.ac.cn) ; Li, Jia(jli@simm.ac.cn) ; Lu, Wei(wlu@chem.ecnu.edu.cn)
英文摘要Proteolysis targeting chimera (PROTAC) technology has received widespread attention in recent years as a promising strategy for drug development. Herein, we report a series of novel Wee1 degraders, which were designed and synthesized based on PROTAC technology by linking AZD1775 with CRBN ligands through linkers of different lengths and types. All degraders could effectively and completely degrade cellular Wee1 protein in MV-4-11 cell line at IC50 concentrations. Preliminary assessments identified 42a as the most active degrader, which possessed potent antiproliferative activity and induced CRBN-and proteasome-dependent degradation of Wee1. Moreover, 42a also exhibited a time-and concentration-dependent depletion manner and inducing cell cycle arrest in G0/G1 phase and cancer cell apoptosis. More importantly, 42a showed acceptable in vitro and in vivo pharmacokinetic properties and displayed rapid and sustained Wee1 degradation ability in vivo. Taken together, these findings contribute to understanding the development of PROTACs and demonstrate that our Wee1-targeting PROTAC strategy has potential novel applications in cancer therapy.
WOS关键词TARGETED PROTEIN-DEGRADATION ; PROTAC ; AZD1775 ; TECHNOLOGY ; CISPLATIN ; POTENT
资助项目Fundamental Research Funds for theCentral Universities ; National Natural Science Foundation of China ; Science and Technology Commission of Shanghai Municipality ; [22077034] ; [82104000] ; [81821005] ; [21S11907500] ; [19430750100]
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:000862466900004
源URL[http://119.78.100.183/handle/2S10ELR8/302601]  
专题新药研究国家重点实验室
通讯作者Zhou, Yubo; Li, Jia; Lu, Wei
作者单位1.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China
2.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Zhongshan 528400, Peoples R China
3.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China
4.Chinese Acad Sci, Shanghai Inst Mat Med, Natl Ctr Drug Screening, State Key Lab Drug Res, Shanghai 201203, Peoples R China
5.East China Normal Univ, Shanghai Engn Res Ctr Mol Therapeut & New Drug Dev, Sch Chem & Mol Engn, 3663 North Zhongshan Rd, Shanghai 200062, Peoples R China
推荐引用方式
GB/T 7714		 Zhu, Shulei,Liu, Jieyu,Xiao, Donghuai,et al. Design, synthesis, and biological evaluation of Wee1 kinase degraders[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2022,243:21.
APA Zhu, Shulei.,Liu, Jieyu.,Xiao, Donghuai.,Wang, Peipei.,Ma, Jingkun.,...&Lu, Wei.(2022).Design, synthesis, and biological evaluation of Wee1 kinase degraders.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,243,21.
MLA Zhu, Shulei,et al."Design, synthesis, and biological evaluation of Wee1 kinase degraders".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 243(2022):21.

入库方式： OAI收割

来源：上海药物研究所

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