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ID: ALA5257149
Journal: ACS Med Chem Lett
Title: Rational Design of Highly Potent and Selective Covalent MAP2K7 Inhibitors.
Authors: Kim DR, Orr MJ, Kwong AJ, Deibler KK, Munshi HH, Bridges CS, Chen TJ, Zhang X, Lacorazza HD, Scheidt KA.
Abstract: The mitogen-activated protein kinase signaling cascade is conserved across eukaryotes, where it plays a critical role in the regulation of activities including proliferation, differentiation, and stress responses. This pathway propagates external stimuli through a series of phosphorylation events, which allows external signals to influence metabolic and transcriptional activities. Within the cascade, MEK, or MAP2K, enzymes occupy a molecular crossroads 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 (T-ALL). Herein, we describe the rational design, synthesis, evaluation, and optimization of a novel class of irreversible MAP2K7 inhibitors. With a streamlined one-pot synthesis, favorable in vitro potency and selectivity, and promising cellular activity, this novel class of compounds wields promise as a powerful tool in the study of pediatric T-ALL.
CiteXplore: 37197477