Advances in JNK inhibitor development: therapeutic prospects in neurodegenerative diseases and fibrosis

Abstract

c-Jun N-terminal kinases (JNKs), a subfamily of mitogen-activated protein kinases (MAPKs), are key mediators of cellular responses to environmental stress, inflammation, and apoptotic signals. The three isoforms - JNK1, JNK2, and JNK3 exhibit both overlapping and isoform-specific functions. While JNK1 and JNK2 are broadly expressed across tissues and regulate immune signaling, cell proliferation, and apoptosis, JNK3 expression is largely restricted to the brain, heart, and testis, where it plays a crucial role in neuronal function and survival. Subtle structural variations among the isoforms, particularly within the ATP-binding pocket and activation loop, provide a basis for the developing isoform-selective inhibitors to improve therapeutic precision. JNK3 has been increasingly recognized for its involvement in the pathogenesis of neurodegenerative disorders, including Alzheimer’s and Parkinson’s diseases, through mechanisms involving neuroinflammation, oxidative stress, and neuronal apoptosis. Given the limited efficacy of current therapies, which remain largely symptomatic and do not modify disease progression, covalent inhibitors of JNK3 represent a compelling alternative due to their potential for high selectivity and sustained target engagement. In parallel, JNK signaling contributes to fibrosis, with JNK1 serving as the predominant isoform driving profibrotic pathways such as fibroblast activation and extracellular matrix (ECM) deposition. Current antifibrotic agents provide only partial benefit and lack specificity for downstream effectors like JNK1. PROteolysis TArgeting Chimeras (PROTACs), which induce selective protein degradation via the ubiquitin-proteasome system, represent a promising modality to overcome these limitations. Selective degradation of JNK1 could provide a novel therapeutic avenue for fibrotic diseases. This review highlights therapeutic efforts to date and discusses how emerging approaches—particularly covalent JNK3 inhibitors for neurodegeneration and PROTACs for JNK1 in fibrosis—may advance future treatment paradigms.