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First ATG101-recruiting small molecule degrader for selective CDK9 degradation via autophagy-lysosome pathway

文献类型：期刊论文

作者Zhong, Ye5; Xu, Jing3,4; Cao, Huiying3; Gao, Jie1,3; Ding, Shaoyue5; Ren, Zhaohui3; Yang, Huali5; Sun, Yili2,3; Cheng, Maosheng5; Li, Jia2,3,4
刊名ACTA PHARMACEUTICA SINICA B
出版日期2025-05-01
卷号15期号:5页码:2612-2624
关键词Protein degradation Hydrophobic tags ATG101 Autophagy-lysosome pathway CDK9 Cyclin T1 Degrader Antitumor
ISSN号2211-3835
DOI10.1016/j.apsb.2025.03.047
通讯作者Sun, Yili(yilisun@simm.ac.cn) ; Cheng, Maosheng(mscheng@syphu.edu.cn) ; Li, Jia(jli@simm.ac.cn) ; Liu, Yang(y.liu@syphu.edu.cn)
英文摘要Cyclin-dependent kinase 9 (CDK9) is a member of the transcription CDK subfamily and plays a role in transcriptional regulation. Selective CDK9 degraders possess potent clinical advantages over reversible CDK9 inhibitors. Herein, we report the first ATG101-recruiting selective CDK9 degrader, AZ-9, based on the hydrophobic tag kinesin degradation technology. AZ-9 showed significant degradation effects and selectivity toward other homologous cell cycle CDKs in vitro and in vivo, which could also affect downstream related phenotypes. Mechanism research revealed that AZ-9 recruits ATG101 to initiate the autophagy-lysosome pathway, and forms autophagosomes through the recruitment of LC3, which then fuses with lysosomes to degrade CDK9 and the partner protein Cyclin T1. These dates validated the existence of non-proteasomal degradation pathway of hydrophobic driven protein degradation strategy for the first time, which might provide research ideas for chemical induction intervention on other types of pathogenic proteins. 2025 The Authors. Published by Elsevier B.V. on behalf of Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
WOS关键词DEPENDENT KINASE INHIBITOR ; DISCOVERY ; PROTACS ; POTENT
资助项目Key R&D Program of Shandong Province, China[2024CXPT028] ; National Natural Science Foundation of China[22177079] ; National Natural Science Foundation of China[22477085] ; National Natural Science Foundation of Shanghai Province, China[24ZR1477400] ; National Natural Science Foundation of Shandong Province, China[ZR2024QC286] ; Taishan Scholar Foundation of Shandong Province[tstp0648]
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001493220400017
出版者INST MATERIA MEDICA, CHINESE ACAD MEDICAL SCIENCES
源URL[http://119.78.100.183/handle/2S10ELR8/317938]  
专题中国科学院上海药物研究所
通讯作者Sun, Yili; Cheng, Maosheng; Li, Jia; Liu, Yang
作者单位1.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Chem Biol, Shanghai 201203, Peoples R China
3.Bohai Rim Adv Res Inst Drug Discovery, Shandong Lab Yantai Drug Discovery, Yantai 264117, Peoples R China
4.Shenyang Pharmaceut Univ, Dept Pharmacol, Shenyang 110016, Peoples R China
5.Shenyang Pharmaceut Univ, Key Lab Struct Based Drug Design & Discovery, Minist Educ, Shenyang 110016, Peoples R China
推荐引用方式
GB/T 7714		 Zhong, Ye,Xu, Jing,Cao, Huiying,et al. First ATG101-recruiting small molecule degrader for selective CDK9 degradation via autophagy-lysosome pathway[J]. ACTA PHARMACEUTICA SINICA B,2025,15(5):2612-2624.
APA Zhong, Ye.,Xu, Jing.,Cao, Huiying.,Gao, Jie.,Ding, Shaoyue.,...&Liu, Yang.(2025).First ATG101-recruiting small molecule degrader for selective CDK9 degradation via autophagy-lysosome pathway.ACTA PHARMACEUTICA SINICA B,15(5),2612-2624.
MLA Zhong, Ye,et al."First ATG101-recruiting small molecule degrader for selective CDK9 degradation via autophagy-lysosome pathway".ACTA PHARMACEUTICA SINICA B 15.5(2025):2612-2624.

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来源：上海药物研究所

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