2. Academic Validation
  3. Design and synthesis of JNK1-targeted PROTACs and research on the activity

Design and synthesis of JNK1-targeted PROTACs and research on the activity

  • Bioorg Chem. 2025 Jan:154:108044. doi: 10.1016/j.bioorg.2024.108044.
Yue Guo 1,  Fengling Liu 2,  Man Chi 2,  Hewen Qian 1,  Ye Zhang 2,  Yaxia Yuan 3,  Shurong Hou 4,  Xiabin Chen 5,  Lei Ma 6
Affiliations

Affiliations

  • 1 Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China.
  • 2 School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China; Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China.
  • 3 Department of Biochemistry and Structural Biology, University of Texas Health Science Center at San Antonio, TX 78229, USA.
  • 4 School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China; Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China. Electronic address: houshurong@hznu.edu.cn.
  • 5 School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China; Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China. Electronic address: xch226@hznu.edu.cn.
  • 6 Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China. Electronic address: malei@ecust.edu.cn.
PMID: 39700830 DOI: 10.1016/j.bioorg.2024.108044
Abstract

Kinase dysregulation is greatly associated with cell growth, proliferation, differentiation and Apoptosis, which indicates their great potential as therapeutic targets for treatment of numerous progressive disorders, including inflammatory, metabolic and autoimmune disorders, organ fibrosis and Cancer. The c‑Jun N‑Terminal Kinase (JNK), as a member of MAPK Family, is proved to be a potential target for the treatment of pulmonary fibrosis, which is the most common progressive and fatal fibrotic lung disease. As a new strategy, small-molecule-mediated targeted protein degradation pathway has the advantages of catalytic properties, overcoming drug resistance and expanding target space, which can circumvent the limitations associated with kinase inhibitors. Proteolysis targeting chimeras (PROTAC) contains a linker to concatenate a ligand of E3 ubiquitin Ligase and a ligand for a protein of interest (POI). We developed a total of 20 JNK1-targeted PROTACs that induce proteasomal degradation of JNK1 components. The most active PROTAC molecule PA2 was then investigated by JNK1 Enzyme assay and protein degradation assay, which suggested that PA2 had an anti-JNK1 ability and provided insights for the future use of JNK1-targeted PROTAC as treatment drugs for pulmonary fibrosis.

Keywords

Degradation potency; Drug discovery; PROTAC; c-Jun N-terminal kinase.

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