2. Academic Validation
  3. Discovery of a selective and potent inhibitor of c-Jun N-terminal kinase 1 with anti-pulmonary fibrosis effect

Discovery of a selective and potent inhibitor of c-Jun N-terminal kinase 1 with anti-pulmonary fibrosis effect

  • Bioorg Med Chem Lett. 2025 Feb 1:116:130044. doi: 10.1016/j.bmcl.2024.130044.
Shuhua Ren 1,  Fengling Liu 2,  Man Chi 2,  Jinfeng Liu 1,  Yi Huang 1,  Weiwei Huang 3,  Wenjing Gu 1,  Yaxia Yuan 4,  Shurong Hou 5,  Xiabin Chen 6,  Lei Ma 7
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 Hangzhou Matrix Biopharmaceutical Co., Ltd, Hangzhou, Zhejiang 311121, China.
  • 4 Department of Biochemistry and Structural Biology, University of Texas Health Science Center at San Antonio, TX 78229, USA.
  • 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: houshurong@hznu.edu.cn.
  • 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: xch226@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.
PMID: 39608686 DOI: 10.1016/j.bmcl.2024.130044
Abstract

We synthesized and evaluated a series of derivatives based on the pyrimidine-2,4-diamine scaffold as potential JNK1 inhibitors, incorporating bridging rings and spirocyclic modifications to enhance their inhibitory activity. These compounds were biologically assessed through JNK Enzyme inhibition assays and Western Blot analysis. Compounds 13, 14 and 19 demonstrated significant inhibitory activity at both the Enzyme and cellular level compared to the lead compound 1 and clinical candidate CC-90001. Notably, 14 exhibited strong inhibitory potency against JNK1 with sub-nanomolar efficacy and suppresses TGF-β-induced epithelial-mesenchymal transition, indicating its potential as a promising candidate for further development as an anti-pulmonary fibrosis agent targeting JNK1.

Keywords

Inhibitor; Pulmonary fibrosis; Pyrimidine-2,4-diamine; c-Jun N-Terminal kinase.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-170420
    JNK1 Inhibitor
    JNK