First ATG101-recruiting small molecule degrader for selective CDK9 degradation via autophagy–lysosome pathway
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, ba...
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| Format: | Article |
| Language: | English |
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Elsevier
2025-05-01
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| Series: | Acta Pharmaceutica Sinica B |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211383525002151 |
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| author | Ye Zhong Jing Xu Huiying Cao Jie Gao Shaoyue Ding Zhaohui Ren Huali Yang Yili Sun Maosheng Cheng Jia Li Yang Liu |
| author_facet | Ye Zhong Jing Xu Huiying Cao Jie Gao Shaoyue Ding Zhaohui Ren Huali Yang Yili Sun Maosheng Cheng Jia Li Yang Liu |
| author_sort | Ye Zhong |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-c816b57d82f745088bdcc01775d5871c |
| institution | DOAJ |
| issn | 2211-3835 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Acta Pharmaceutica Sinica B |
| spelling | doaj-art-c816b57d82f745088bdcc01775d5871c2025-08-20T03:09:59ZengElsevierActa Pharmaceutica Sinica B2211-38352025-05-011552612262410.1016/j.apsb.2025.03.047First ATG101-recruiting small molecule degrader for selective CDK9 degradation via autophagy–lysosome pathwayYe Zhong0Jing Xu1Huiying Cao2Jie Gao3Shaoyue Ding4Zhaohui Ren5Huali Yang6Yili Sun7Maosheng Cheng8Jia Li9Yang Liu10Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, ChinaDepartment of Pharmacology, Shenyang Pharmaceutical University, Shenyang 110016, China; Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai 264117, ChinaShandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai 264117, ChinaShandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai 264117, China; School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, ChinaKey Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, ChinaShandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai 264117, ChinaKey Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, ChinaShandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai 264117, China; State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; Corresponding authors.Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China; Corresponding authors.Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang 110016, China; Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai 264117, China; State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; Corresponding authors.Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China; Corresponding authors.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.http://www.sciencedirect.com/science/article/pii/S2211383525002151Protein degradationHydrophobic tagsATG101Autophagy–lysosome pathwayCDK9Cyclin T1 |
| spellingShingle | Ye Zhong Jing Xu Huiying Cao Jie Gao Shaoyue Ding Zhaohui Ren Huali Yang Yili Sun Maosheng Cheng Jia Li Yang Liu First ATG101-recruiting small molecule degrader for selective CDK9 degradation via autophagy–lysosome pathway Acta Pharmaceutica Sinica B Protein degradation Hydrophobic tags ATG101 Autophagy–lysosome pathway CDK9 Cyclin T1 |
| title | First ATG101-recruiting small molecule degrader for selective CDK9 degradation via autophagy–lysosome pathway |
| title_full | First ATG101-recruiting small molecule degrader for selective CDK9 degradation via autophagy–lysosome pathway |
| title_fullStr | First ATG101-recruiting small molecule degrader for selective CDK9 degradation via autophagy–lysosome pathway |
| title_full_unstemmed | First ATG101-recruiting small molecule degrader for selective CDK9 degradation via autophagy–lysosome pathway |
| title_short | First ATG101-recruiting small molecule degrader for selective CDK9 degradation via autophagy–lysosome pathway |
| title_sort | first atg101 recruiting small molecule degrader for selective cdk9 degradation via autophagy lysosome pathway |
| topic | Protein degradation Hydrophobic tags ATG101 Autophagy–lysosome pathway CDK9 Cyclin T1 |
| url | http://www.sciencedirect.com/science/article/pii/S2211383525002151 |
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