p38 mitogen-activated protein kinase: Functions and targeted therapy in diseases

P38 mitogen-activated protein kinase (p38MAPK) is a multifunctional protein kinase that plays an important role in human normal physiological activities and a variety of major diseases, and its signaling pathway affects a variety of regulatory factors in vivo, which is related to cell cycle, survival, metabolism, and differentiation. The four subtypes of p38MAPK have significant differences in their distribution, content, and effects in the body. The inhibitors of the four subtypes play potential roles in regulating cancer, neurodegenerative diseases, inflammation, and cardiovascular diseases, making it an attractive target for drug development. So far, an increasing number of p38MAPK inhibitors have been developed for targeted therapy in diseases, among which some representative compounds have entered clinical trials. Therefore, this review aims to provide a summary of the structural characteristics, signaling pathways of P38MAPK and the relationship between p38MAPK and disease, along with an overview of the binding modes and structure-activity relationships of small molecule inhibitors targeting four p38MAPK subtypes, and summarizes the challenges about the development of p38MAPK inhibitors, hoping to provide a valuable reference for the development and application of novel inhibitors. Our review provides an overview of the relationship between P38 mitogen-activated protein kinase (p38MAPK) and disease, especially on small-molecule inhibitors of four p38MAPK subtypes, and summarizes the challenges about the development of p38MAPK inhibitors. image