Language
English
Publication Date
5-11-2023
Journal
ACS Medicinal Chemistry Letters
DOI
10.1021/acsmedchemlett.3c00029
PMID
37197477
PMCID
PMC10184151
PubMedCentral® Posted Date
4-17-2023
PubMedCentral® Full Text Version
Post-print
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.
Keywords
mitogen-activated protein kinases, drug discovery, small molecule inhibitors, lead optimization, covalent inhibitors, irreversible inhibitors, T cell acute lymphoblastic leukemia, MAP2K7, MEK7, MKK7
Published Open-Access
yes
Recommended Citation
Kim, Dalton R; Orr, Meghan J; Kwong, Ada J; et al., "Rational Design of Highly Potent and Selective Covalent MAP2K7 Inhibitors" (2023). Faculty and Staff Publications. 5611.
https://digitalcommons.library.tmc.edu/baylor_docs/5611
Graphical Abstract
Included in
Allergy and Immunology Commons, Biological Phenomena, Cell Phenomena, and Immunity Commons, Pathology Commons