Discovery of 2,4-quinazolinedione derivatives as LC3B recruiters in the facilitation of protein complex degradations
文献类型：期刊论文
| 作者 | Zeng, Yanping7,8; Xiao, Jian4,7; Shi, Li6; Li, Yangsha4,7; Xu, Yuanxin5; Zhou, Jiayun2; Dong, Xiao4,7; Hou, Haiyang4,7; Zhong, Chao2; Cheng, Gang1 |
| 刊名 | EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
 |
| 出版日期 | 2025-04-05 |
| 卷号 | 287页码:10 |
| 关键词 | LC3B CDK9 Degradation Protein complex |
| ISSN号 | 0223-5234 |
| DOI | 10.1016/j.ejmech.2025.117293 |
| 英文摘要 | Targeted protein degradation through autophagosome-tethering compounds (ATTECs) that bypasses the ubiquitination process has garnered increasing attention. LC3B, a key protein in autophagosome formation, recruits substrates into the autophagy-lysosome system for degradation. In this study, we systematically optimized 2,4quinazolinedione derivatives as LC3B-recruiting fragments, utilizing the CDK9 indicator. By attaching the designed LC3B-recruiting fragment to CDK9 inhibitor SNS-032 through a linker, the resulting bifunctional ATTEC molecule simultaneously degraded CDK9 and its associated Cyclin T1. Two-dimensional NMR experiments confirmed the direct interaction between the novel LC3B-recruiting fragments and LC3B. Mechanistic studies elucidated that degradation occurred via an LC3B-dependent autophagy-lysosomal pathway. Additionally, the general applicability of leveraging LC3B-recruiting fragments linked to inhibitors for the targeted degradation of protein complexes was validated with PRC2 and CDK2/4/6 along with their respective Cyclins. This work provides a series of novel LC3B-recruiting fragments that enrich the ATTEC toolbox and can be applied to the degradation of diverse intracellular disease-causing proteins. |
| WOS关键词 | ADVANCED BREAST-CANCER ; CELL-CYCLE ; INHIBITION ; ADAPTATION ; PRC2 ; EZH1 ; CDK2 |
| 资助项目 | Shanghai Institute of Materia Medica, Chinese Academy of Sciences[SIMM0220232002] ; National Natural Science Foundation of China[22477126] ; National Natural Science Foundation of China[32171220] |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:001425128500001 |
| 出版者 | ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/316278]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Zhang, Naixia; Fang, Yanfen; Hu, Youhong |
| 作者单位 | 1.Zhejiang Chinese Med Univ, Sch Pharmaceut Sci, Hangzhou 311402, Peoples R China 2.Fudan Univ, Sch Life Sci, Jiangwan Campus,2005 Songhu Rd, Shanghai 200433, Peoples R China 3.Bohai Rim Adv Res Inst Drug Discovery, Shandong Lab Yantai Drug Discovery, Yantai 264117, Shandong, Peoples R China 4.Univ Chinese Acad Sci, 19 Yuquan Rd, Beijing 110039, Peoples R China 5.Nanjing Univ Chinese Med, Sch Chinese Mat Med, 138 Xianlin Rd, Nanjing 210046, Peoples R China 6.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Chem Biol, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China 7.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China 8.Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, 1 Xiangshanzhi Rd, Hangzhou 310024, Peoples R China |
| 推荐引用方式 GB/T 7714 | Zeng, Yanping,Xiao, Jian,Shi, Li,et al. Discovery of 2,4-quinazolinedione derivatives as LC3B recruiters in the facilitation of protein complex degradations[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2025,287:10. |
| APA | Zeng, Yanping.,Xiao, Jian.,Shi, Li.,Li, Yangsha.,Xu, Yuanxin.,...&Hu, Youhong.(2025).Discovery of 2,4-quinazolinedione derivatives as LC3B recruiters in the facilitation of protein complex degradations.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,287,10. |
| MLA | Zeng, Yanping,et al."Discovery of 2,4-quinazolinedione derivatives as LC3B recruiters in the facilitation of protein complex degradations".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 287(2025):10. |
入库方式： OAI收割
来源：上海药物研究所
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