1 research outputs found
Rational Design of Highly Potent and Selective Covalent MAP2K7 Inhibitors
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