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The evolution of JNK inhibition: A review on modern targeting strategies

Jie Li1, Lin Cao2, Yinglai Yang1

  • 1Xinjiang Second Medical College, Karamay, 834000, People's Republic of China.

European Journal of Medicinal Chemistry
|March 27, 2026
PubMed

Insights

Targeting the c-Jun N-terminal kinase (JNK) pathway has shifted from broad inhibition to isoform-selective strategies. This approach aims to overcome toxicity and improve efficacy for various diseases by understanding JNK biology.

Area of Science:

  • Cellular Biology
  • Molecular Pharmacology
  • Drug Discovery

Background:

  • The c-Jun N-terminal kinase (JNK) pathway is crucial for cellular stress responses and disease pathogenesis.
  • Previous pan-JNK inhibition strategies failed due to poor selectivity and toxicity, linked to JNK isoform diversity (JNK1, JNK2, JNK3).

Purpose of the Study:

  • To review the paradigm shift in JNK-targeted therapeutics from pan-inhibition to precision strategies.
  • To provide a comprehensive overview of JNK signaling, isoform structures, and disease-specific roles.
  • To highlight emerging therapeutic modalities for JNK pathway modulation.

Main Methods:

  • Literature review of JNK signaling pathways and therapeutic strategies.
  • Analysis of JNK isoform structure-function relationships.
  • Overview of novel drug development approaches including isoform-selective inhibitors, allosteric modulators, PROTACs, and photo-controlled inhibitors.

Main Results:

  • The JNK pathway's complexity necessitates isoform-specific targeting for therapeutic benefit.
  • Emerging strategies like isoform-selective inhibitors and PROTACs offer improved selectivity and reduced toxicity.
  • Understanding context-dependent JNK roles is key for rational drug design.

Conclusions:

  • A precision-targeting approach is essential for developing effective JNK-based therapeutics.
  • Future JNK drug development should focus on isoform selectivity and novel modalities.
  • Strategic insights are provided for designing next-generation JNK pathway therapeutics.
Keywords:
Allosteric inhibitorIsoform selectivityJNK

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