Unraveling the Design and Discovery of c-Jun N-Terminal Kinase Inhibitors and Their Therapeutic Potential in Human Diseases.

c-Jun N-terminal kinases (JNKs), members of the mitogen-activated protein kinase (MAPK) family, are encoded by three genes: jnk1 , jnk2 , and jnk3 . JNKs are involved in the pathogenesis and development of many diseases, such as neurodegenerative diseases, inflammation, and cancers. Therefore, JNKs have become important therapeutic targets. Many JNK inhibitors have been discovered, and some have been introduced into clinical trials. However, the study of isoform-selective JNK inhibitors is still a challenging task. To further develop novel JNK inhibitors with clinical value, a comprehensive understanding of JNKs and their corresponding inhibitors is required. In this Perspective, we introduced the JNK signaling pathways and reviewed different chemical types of JNK inhibitors, focusing on their structure-activity relationships and biological activities. The challenges and strategies for the development of JNK inhibitors are also discussed. It is hoped that this Perspective will provide valuable references for the development of novel selective JNK inhibitors.