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

The c-Jun N-terminal kinase (JNK) signaling pathway serves as a central mediator of cellular stress responses and plays a pivotal role in the pathogenesis of a broad spectrum of diseases. Early drug discovery efforts prioritized pan-JNK inhibition, but this strategy failed in clinical development due to inadequate kinase selectivity and unacceptable toxicities, largely stemming from the complex biology and functional diversity of the three JNK isoforms (JNK1, JNK2, and JNK3). This review highlights the field's paradigm shift toward precision-targeted therapeutic strategies. We provide a comprehensive overview of the JNK signaling cascade, the structural features of JNK isoforms, and their context-dependent pharmacological roles across disease states. Emphasis is placed on emerging approaches, including isoform-selective inhibitors, allosteric modulators, and novel therapeutic modalities such as PROTACs and photo-controlled inhibitors. Finally, we offer strategic insights to guide the rational design and development of next-generation therapeutics targeting the JNK pathway.