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Degradation of Cyclin-Dependent Kinase 9/Cyclin T1 by Optimized Microtubule-Associated Protein 1 Light Chain 3 Beta-Recruiting Coumarin Analogs

文献类型：期刊论文

作者Zeng, Yanping2,5; Xiao, Jian3,5; Xu, Yuanxin4; Wei, Fan3; Tian, Lina4; Gao, Yinglei3; Chen, Yi2,3,5,6,7; Hu, Youhong1,2,4,5,6
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2023-09-06
页码17
ISSN号0022-2623
DOI10.1021/acs.jmedchem.3c00828
通讯作者Chen, Yi(ychen@simm.ac.cn) ; Hu, Youhong(yhhu@simm.ac.cn)
英文摘要Autophagy is an efficient and attractive protein degradation pathway in addition to the ubiquitin-proteasome system. Herein, systematic optimization of coumarin analogs linked with the CDK9 inhibitor SNS-032 is reported that may bind to cyclin-dependent kinase 9 (CDK9) and microtubule-associated protein 1 light chain 3 beta (LC3B) simultaneously, which leads to the selective autophagic degradation of targeted CDK9/cyclin T1 and is different from the PROTAC degrader THAL-SNS-032. Further mechanism studies revealed an autophagy-lysosome pathway, where the degraders possibly formed a ternary complex with CDK9 and LC3B. In addition, degrader 10 showed antitumor efficacy in vivo. Our work optimized a potent LC3B recruiter and demonstrated the feasibility of autophagy-tethering compounds (ATTECs), which could be applied for the degradation of diverse intracellular pathogenic proteins to treat related diseases.
WOS关键词AUTOPHAGY ; INHIBITORS ; CDK9
资助项目State Key Laboratory of Drug Research[SIMM2205KF-04] ; Shanghai Academic Research Leader[22XD1404400]
WOS研究方向Pharmacology & Pharmacy
语种英语
出版者AMER CHEMICAL SOC
WOS记录号WOS:001063135800001
源URL[http://119.78.100.183/handle/2S10ELR8/306164]  
专题新药研究国家重点实验室
通讯作者Chen, Yi; Hu, Youhong
作者单位1.Univ Chinese Acad Sci, Chinese Acad Sci, Hangzhou Inst Adv Study, Hangzhou 310024, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
3.Chinese Acad Sci, Div Antitumor Pharmacol, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
4.Nanjing Univ Chinese Med, Nanjing 210046, Jiangsu, Peoples R China
5.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
6.Bohai Rim Adv Res Inst Drug Discovery, Shandong Lab Yantai Drug Discovery, Yantai 264117, Shandong, Peoples R China
7.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Chem Biol, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Zeng, Yanping,Xiao, Jian,Xu, Yuanxin,et al. Degradation of Cyclin-Dependent Kinase 9/Cyclin T1 by Optimized Microtubule-Associated Protein 1 Light Chain 3 Beta-Recruiting Coumarin Analogs[J]. JOURNAL OF MEDICINAL CHEMISTRY,2023:17.
APA Zeng, Yanping.,Xiao, Jian.,Xu, Yuanxin.,Wei, Fan.,Tian, Lina.,...&Hu, Youhong.(2023).Degradation of Cyclin-Dependent Kinase 9/Cyclin T1 by Optimized Microtubule-Associated Protein 1 Light Chain 3 Beta-Recruiting Coumarin Analogs.JOURNAL OF MEDICINAL CHEMISTRY,17.
MLA Zeng, Yanping,et al."Degradation of Cyclin-Dependent Kinase 9/Cyclin T1 by Optimized Microtubule-Associated Protein 1 Light Chain 3 Beta-Recruiting Coumarin Analogs".JOURNAL OF MEDICINAL CHEMISTRY (2023):17.

入库方式： OAI收割

来源：上海药物研究所

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