2. Academic Validation
  3. Structure Optimization of c-Jun N-terminal Kinase 1 Inhibitors for Treating Idiopathic Pulmonary Fibrosis

Structure Optimization of c-Jun N-terminal Kinase 1 Inhibitors for Treating Idiopathic Pulmonary Fibrosis

  • J Med Chem. 2024 Oct 10;67(19):17713-17737. doi: 10.1021/acs.jmedchem.4c01764.
Yi Huang 1,  Fengling Liu 2 3,  Shuhua Ren 1,  Yuanqing Ding 2 3,  Man Chi 2 3,  Weiwei Huang 4,  Wenjing Gu 1,  Hewen Qian 1,  Yaxia Yuan 5,  Shurong Hou 2 3,  Xiabin Chen 2 3,  Lei Ma 1
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.
  • 3 Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, and 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 Department of Biochemistry and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, United States.
PMID: 39303278 DOI: 10.1021/acs.jmedchem.4c01764
Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive and lethal lung disease with an elusive etiology. Aberrant activation of c-Jun N-terminal kinase 1 (JNK1) has been implicated in its pathogenesis. Through a combination of structure-based drug design and structure-activity relationship (SAR) optimization, a series of pyrimidine-2,4-diamine scaffold derivatives have been developed as potent JNK1 inhibitors. Compound E1 was identified with low nanomolar JNK1 inhibitory potency (IC50 = 2.7 nM). The introduction of a dimethylamine side chain has significantly enhanced the ability of E1 to inhibit c-Jun phosphorylation, surpassing the clinical candidate CC-90001. Molecular dynamics simulations revealed a binding free energy of -50.46 kcal/mol for E1. Moreover, E1 displayed satisfactory pharmacokinetic properties, with a bioavailability of 69% in rats. Furthermore, compound E1 exerted significant antifibrotic effects in a bleomycin-induced IPF mouse model and prevented a TGF-β-induced epithelial-to-mesenchymal transition in vitro. These findings position E1 as a promising lead for further drug development targeting IPF.

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