The Rational Design of Highly Potent and Selective Covalent MAP2K7 Inhibitors

The mitogen-activated protein kinase signaling cascade is conserved across eukaryotes from yeast to humans, where it plays a central role regulating activities including proliferation, differentiation, and stress responses. This pathway propagates external stimuli through a series of phosphorylation events, allowing external signals to influence metabolic and transcriptional activities. Within the cascade, MEK, or MAP2K, enzymes occupy a molecular crossroads situated immediately upstream to significant signal divergence and cross-talk. One such kinase, MAP2K7, also known as MEK7 and MKK7, is a protein of great interest in the molecular pathophysiology underlying pediatric T-cell acute lymphoblastic leukemia. Herein, we describe the rational design, synthesis, evaluation, and optimization of a novel class of irre-versible MAP2K7 inhibitors. With a streamlined one-pot synthesis, favorable in vitro potency and selectivity, as well as promising cellular activity, this novel class of compounds wields promise as a powerful tool in the study of pediatric T-ALL