2. Academic Validation
  3. Design, synthesis, and biological evaluation of novel hydrophobic tag-based degraders targeting JNK1

Design, synthesis, and biological evaluation of novel hydrophobic tag-based degraders targeting JNK1

  • Bioorg Chem. 2026 Jun 15:174:109756. doi: 10.1016/j.bioorg.2026.109756.
Yi Huang 1,  Man Chi 2,  Ye Zhang 2,  Weiqi Cai 2,  Weiwei Huang 3,  Shuhua Ren 4,  Wenjing Gu 4,  Yaxia Yuan 5,  Shurong Hou 6,  Lei Ma 7,  Xiabin Chen 8
Affiliations

Affiliations

  • 1 State Key Laboratory of Analytical Chemistry for Life Science, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, Jiangsu 210023, China; 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: 20243016@hznu.edu.cn.
  • 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 Hangzhou Matrix Biopharmaceutical Co., Ltd, Hangzhou, Zhejiang 311121, China.
  • 4 Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China.
  • 5 Department of Biochemistry and Structural Biology, University of Texas Health Science Center at San Antonio, TX 78229, USA.
  • 6 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.
  • 7 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.
  • 8 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.
PMID: 41856067 DOI: 10.1016/j.bioorg.2026.109756
Abstract

The epithelial-mesenchymal transition (EMT) plays a pivotal role in embryonic development and tissue repair. However, dysregulated EMT contributes to fibrotic disorders and Cancer metastasis. JNK1 is recognized as a core regulator of TGF-β-induced EMT, positioning it as a therapeutic target for EMT-associated pathologies. Here, we report the first application of hydrophobic tag (HyT) technology, a targeted protein degradation (TPD) strategy, to develop JNK1 degraders. A series of HyT-based degraders was designed and synthesized by conjugating the JNK1 Inhibitor A3 to structurally distinct hydrophobic moieties. Compound HY12 emerged as a potent degrader, inducing dose- and time-dependent JNK1 degradation. Mechanistic studies revealed that both the ubiquitin-proteasome system (UPS) and the autophagy-lysosome pathway contribute to HY12-mediated JNK1 degradation. Furthermore, HY12 effectively inhibited TGF-β1-induced EMT. This work establishes a novel HyT-mediated JNK1 degradation platform and provides a promising therapeutic strategy for EMT-associated disorders.

Keywords

C-Jun N-terminal kinase; Epithelial-mesenchymal transition; Hydrophobic tagging; Protein degradation.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z