Explaining Isoform Selectivity of c-Jun N-Terminal Kinase 3 (JNK3) Inhibitors through Its Development and Structural Insights

c-Jun N-terminal kinase 3 (JNK3), a member of the mitogen-activated protein kinase (MAPK) family, is selectively enriched in the brain. It plays a significant role in the pathogenesis of neurodegenerative disorders, glaucoma, amyotrophic lateral sclerosis, and cancer, which makes it a promising drug target. However, the advancement of JNK3 inhibitors has been challenged by limited isoform selectivity. This article explains the pathway regulated by JNK3 and the unique functions of JNK3. A detailed structural analysis of JNK3 complexes with ligands is presented to uncover the molecular basis of binding interactions. The inhibitors are systematically classified according to their chemical scaffolds, and the reason for their isoform selectivity was discussed, providing a structural rationale for the evolution of JNK3 inhibitor design. The perspective concludes with an exploration of the challenges in the discovery of selective JNK3 inhibitors and proposes innovative strategies to surmount these obstacles.