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

Yi Huang1, Fengling Liu2,3, Shuhua Ren1

  • 1Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China.

Journal of Medicinal Chemistry
|September 20, 2024
PubMed

Insights

A novel JNK1 inhibitor, compound E1, shows significant potential for treating idiopathic pulmonary fibrosis (IPF). It effectively reduces fibrosis in mouse models and inhibits key disease pathways.

Area of Science:

  • Medicinal Chemistry
  • Pharmacology
  • Pulmonary Medicine

Background:

  • Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease with unknown causes.
  • Aberrant activation of c-Jun N-terminal kinase 1 (JNK1) is linked to IPF development.
  • Targeting JNK1 offers a potential therapeutic strategy for IPF.

Purpose of the Study:

  • To design and synthesize novel pyrimidine-2,4-diamine derivatives as potent JNK1 inhibitors.
  • To evaluate the efficacy of compound E1 in preclinical models of IPF.
  • To assess the pharmacokinetic and antifibrotic properties of compound E1.

Main Methods:

  • Structure-based drug design and structure-activity relationship (SAR) optimization were employed.
  • Compound E1 was synthesized and characterized for its JNK1 inhibitory potency (IC50).
  • In vitro and in vivo studies included molecular dynamics simulations, pharmacokinetic analysis, and assessment in bleomycin-induced IPF mouse models and TGF-β assays.

Main Results:

  • Compound E1 demonstrated low nanomolar JNK1 inhibitory potency (IC50 = 2.7 nM).
  • E1 exhibited superior inhibition of c-Jun phosphorylation compared to CC-90001.
  • Molecular dynamics simulations predicted a binding free energy of -50.46 kcal/mol for E1.
  • E1 showed good bioavailability (69% in rats) and significant antifibrotic effects in vivo and in vitro.

Conclusions:

  • Compound E1 is a potent JNK1 inhibitor with promising antifibrotic activity.
  • E1 displays favorable pharmacokinetic properties, making it a potential drug candidate for IPF.
  • Further development of E1 could lead to a novel therapeutic agent for idiopathic pulmonary fibrosis.

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