Small-molecule inhibitors targeting apoptosis signal-regulated kinase 1

Apoptosis signal regulated kinase 1 (ASK1, also known as MAP3K5) is a member of the mitogen activated protein kinase kinase kinase (MAP3K) family. Since its first isolation from a human macrophage library in 1996, its research has been ongoing for over 25 years. A large number of reports have revealed that ASK1, as a key activator of the p38 mitogen-activated protein kinase and c-Jun N-terminal kinase (JNK) signaling cascade, responds to various stressors, and its inhibitors have important potential value in the treatment of diseases such as inflammation, cancer, and the nervous system and so on. This review summarizes the recent development in this field, including the structure and signaling pathways of ASK1, with a particular focus on the structure-activity relationships, and the hit-to-lead optimization strategies.