Synthesis-accessibility-oriented design of c-Jun N-terminal kinase 1 inhibitor

  • Eur J Med Chem. 2023 Aug 5;256:115442. doi: 10.1016/j.ejmech.2023.115442.
Hewen Qian  1 ,  Yuanqing Ding  2 ,  Xingyu Deng  3 ,  Weiwei Huang  4 ,  Zhenzhen Li  2 ,  Fengling Liu  2 ,  Jie Zhang  2 ,  Lihui Wang  5 ,  Junping Liu  5 ,  Yaxia Yuan  6 ,  Shurong Hou  7 ,  Xiabin Chen  8 ,  Lei Ma  9
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. Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai, 200237, 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.
  • 4. Hangzhou Matrix Biopharmaceutical Co., Ltd, Hangzhou, Zhejiang, 311121, China.
  • 5. Institute of Ageing Research, Hangzhou Normal University, School of Medicine, Hangzhou, Zhejiang Province, 311121, China.
  • 6. Department of Biochemistry and Structural Biology, University of Texas Health Science Center at San Antonio, Texas, 78229, USA.
  • 7. 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: [email protected].
  • 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: [email protected].
  • 9. 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: [email protected].
PMID: 37156184 DOI: 10.1016/j.ejmech.2023.115442
Abstract

Idiopathic pulmonary fibrosis (IPF) is a severe and progressive lung disease with poor prognosis and limited treatment options. The c-Jun N-Terminal Kinase 1 (JNK1), a key component of the MAPK pathway, has been implicated in the pathogenesis of IPF and represents a potential therapeutic target. However, the development of JNK1 inhibitors has been slowed, partly due to synthetic complexity in medicinal chemistry modification. Here, we report a synthesis-accessibility-oriented strategy for designing JNK1 inhibitors based on computational prediction of synthetic feasibility and fragment-based molecule generation. This strategy led to the discovery of several potent JNK1 inhibitors, such as compound C6 (IC50 = 33.5 nM), which exhibited comparable activity to the clinical candidate CC-90001 (IC50 = 24.4 nM). The anti-fibrotic effect of C6 was further confirmed in animal model of pulmonary fibrosis. Moreover, compound C6 could be synthesized in only two steps, compared to nine steps for CC-90001. Our findings suggest that compound C6 is a promising lead for further optimization and development as a novel anti-fibrotic agent targeting JNK1. In addition, the discovery of C6 also demonstrates the feasibility of synthesis-accessibility-oriented strategy in lead discovery.

Keywords
Fragment-based drug design; Idiopathic pulmonary fibrosis; Inhibitor; Pyrimidine-2,4-diamine; Structure-activity relationship; Synthesis-accessibility; c-Jun N-Terminal kinase.
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