2. Academic Validation
  3. Synthesis-accessibility-oriented design of c-Jun N-terminal kinase 1 inhibitor

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

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: houshurong@hznu.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.
  • 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: malei@ecust.edu.cn.
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.

Figures
Products