MAP4K3/GLK: Structure, molecular pharmacology and drug development

GLK (also known as MAP4K3), classified as a member of the MAP4K family, is a Ste20-like serine/threonine kinase. GLK plays a pivotal role in multiple cellular signaling pathways, including TCR-mediated immune responses, as well as the JNK, mTOR, and NF-κB signaling pathways. Due to its critical role in these key regulatory networks, GLK has been implicated in the pathogenesis of various diseases, including autoimmune diseases, cancer, aging, and COVID-19 infection. Consequently, GLK represents a promising molecular target for the development of novel therapeutic interventions for immunotherapy and oncotherapy. This review comprehensively summarizes the signaling pathways and human diseases regulated by GLK, focusing on GLK protein kinase structure, GLK-specific regulators, and profiling strategies for developing GLK-specific small-molecule inhibitors.