中国科学院机构知识库网格
Chinese Academy of Sciences Institutional Repositories Grid
首页 机构 成果 学者
  
  1. CAS IR Grid
  2. 上海药物研究所
  3. 中国科学院上海药物研究所
Discovery of TBK1Molecular Glue Degraders as a Potential Strategy for the Treatment of Autosomal Dominant Polycystic Kidney Disease (ADPKD)

文献类型：期刊论文

作者Guo, Jing5; Tang, Haotian3,4; Zhao, Wenchao2; Li, Yong5; Song, Shukai5; Feng, Fang4; Huang, Shengjie5; Wang, Xuan5; Zhou, Yang5; Pei, Junping5
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2025-06-06
卷号68期号:12页码:12862-12880
ISSN号0022-2623
DOI10.1021/acs.jmedchem.5c00722
通讯作者Guo, Dong(guo@xzhmu.edu.cn) ; Xie, Hua(hxie@simm.ac.cn) ; Lu, Xiaoyun(luxy2016@jnu.edu.cn)
英文摘要Autosomal dominant polycystic kidney disease (ADPKD) causes progressive cyst formation and renal failure. Tank-binding kinase 1 (TBK1), a key regulator of inflammation, represents a promising target for ADPKD treatment. In this study, we designed and synthesized a series of TBK1 degraders, including both PROTACs and molecular glues. Among the compounds evaluated, degrader 30 demonstrated superior efficacy, inducing TBK1 degradation in a dose- and time-dependent manner. Mechanistic studies revealed that 30 mediates TBK1 degradation through the ubiquitin-proteasome system via E3 ligase RNF126. Compound 30 effectively inhibited cyst growth and alleviated inflammation in MDCK cysts and in a kidney-specific Pkd1 knockout mouse model. Treatment with 30 reduced the levels of key inflammatory markers, such as Ccl2, IFN beta, and IL-6, which are implicated in ADPKD pathogenesis. These findings highlight the therapeutic potential of TBK1 degradation as a novel strategy for treating ADPKD by simultaneously targeting cyst formation and inflammation.
WOS关键词TBK1 ; TARGET ; DERIVATIVES ; ACTIVATION ; INHIBITOR ; PATHWAY ; CANCER ; BX795
资助项目Guangdong Provincial Department of Science and Technology[2024B1515040007] ; Guangdong Provincial Department of Science and Technology[2022B1515130008] ; Guangdong Provincial Department of Science and Technology[2024A1515012846] ; Guangdong Basic and Applied Basic Research Foundation[GZNL2024A01011] ; Changjiang Scholars Award Program of Ministry of Education, Major Project of Guangzhou National Laboratory Grant[2024A04J4259] ; Youth Doctor Start Program of the Guangdong Science and Technology Bureau ; High-Performance Public Computing Service Platform of Jinan University
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001503222700001
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/318216]  
专题中国科学院上海药物研究所
通讯作者Guo, Dong; Xie, Hua; Lu, Xiaoyun
作者单位1.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
2.Xuzhou Med Univ, Jiangsu Key Lab New Drug Res & Clin Pharm, Xuzhou 221004, Jiangsu, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, Mol Drug Res Ctr, Div Antitumor Pharmacol & Small, Shanghai 201203, Peoples R China
4.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Zhongshan 528400, Peoples R China
5.Jinan Univ, Sch Pharm, State Key Lab Bioact Mol & Druggabil Assessment, Minist Educ,Guangzhou City Key Lab Precis Chem Dru, Guangzhou 510632, Peoples R China
推荐引用方式
GB/T 7714		 Guo, Jing,Tang, Haotian,Zhao, Wenchao,et al. Discovery of TBK1Molecular Glue Degraders as a Potential Strategy for the Treatment of Autosomal Dominant Polycystic Kidney Disease (ADPKD)[J]. JOURNAL OF MEDICINAL CHEMISTRY,2025,68(12):12862-12880.
APA Guo, Jing.,Tang, Haotian.,Zhao, Wenchao.,Li, Yong.,Song, Shukai.,...&Lu, Xiaoyun.(2025).Discovery of TBK1Molecular Glue Degraders as a Potential Strategy for the Treatment of Autosomal Dominant Polycystic Kidney Disease (ADPKD).JOURNAL OF MEDICINAL CHEMISTRY,68(12),12862-12880.
MLA Guo, Jing,et al."Discovery of TBK1Molecular Glue Degraders as a Potential Strategy for the Treatment of Autosomal Dominant Polycystic Kidney Disease (ADPKD)".JOURNAL OF MEDICINAL CHEMISTRY 68.12(2025):12862-12880.

入库方式： OAI收割

来源：上海药物研究所

浏览0
下载0
收藏0
其他版本

除非特别说明，本系统中所有内容都受版权保护，并保留所有权利。