2. Academic Validation
  3. Discovery of TBK1Molecular Glue Degraders as a Potential Strategy for the Treatment of Autosomal Dominant Polycystic Kidney Disease (ADPKD)

Discovery of TBK1Molecular Glue Degraders as a Potential Strategy for the Treatment of Autosomal Dominant Polycystic Kidney Disease (ADPKD)

  • J Med Chem. 2025 Jun 26;68(12):12862-12880. doi: 10.1021/acs.jmedchem.5c00722.
Jing Guo 1,  Haotian Tang 2 3,  Wenchao Zhao 4,  Yong Li 1,  Shukai Song 1,  Fang Feng 2,  Shengjie Huang 1,  Xuan Wang 1,  Yang Zhou 1,  Junping Pei 1,  Dong Guo 4,  Hua Xie 2 3 5,  Xiaoyun Lu 1
Affiliations

Affiliations

  • 1 State Key Laboratory of Bioactive Molecules and Druggability Assessment, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education, Guangzhou City Key Laboratory of Precision Chemical Drug Development, School of Pharmacy, Jinan University, Guangzhou 510632, China.
  • 2 Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528400, China.
  • 3 Division of Antitumor Pharmacology & Small-Molecule Drug Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 4 Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China.
  • 5 University of Chinese Academy of Sciences, Beijing 100049, China.
PMID: 40474483 DOI: 10.1021/acs.jmedchem.5c00722
Abstract

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, IFNβ, 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.

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