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

被引：13

作者：

Zeng, Yanping ^{[1
,4
]}

Xiao, Jian ^{[2
,4
]}

Xu, Yuanxin ^{[3
]}

Wei, Fan ^{[2
]}

Tian, Lina ^{[3
]}

Gao, Yinglei ^{[2
]}

Chen, Yi ^{[1
,2
,4
,5
,7
]}

Hu, Youhong ^{[1
,3
,4
,5
,6
]}

机构：

[1] Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China

[2] Chinese Acad Sci, Div Antitumor Pharmacol, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China

[3] Nanjing Univ Chinese Med, Nanjing 210046, Jiangsu, Peoples R China

[4] Univ Chinese Acad Sci, Beijing 100049, Peoples R China

[5] Bohai Rim Adv Res Inst Drug Discovery, Shandong Lab Yantai Drug Discovery, Yantai 264117, Shandong, Peoples R China

[6] Univ Chinese Acad Sci, Chinese Acad Sci, Hangzhou Inst Adv Study, Hangzhou 310024, Peoples R China

[7] Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Chem Biol, Shanghai 201203, Peoples R China

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2023年 / 66卷 / 18期

关键词：

AUTOPHAGY; INHIBITORS; CDK9;

D O I：

10.1021/acs.jmedchem.3c00828

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

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.

引用

页码：12877 / 12893

页数：17

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