The Rational Design of Highly Potent and Selective Covalent MAP2K7 Inhibitors

23 January 2023, Version 1
This content is a preprint and has not undergone peer review at the time of posting.

Abstract

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

Keywords

mitogen-activated protein kinases
T-cell acute lymphoblastic leukemia
drug discover

Supplementary materials

Title
Description
Actions
Title
Supporting Information
Description
Experimental procedures and protocols.
Actions

Comments

Comments are not moderated before they are posted, but they can be removed by the site moderators if they are found to be in contravention of our Commenting Policy [opens in a new tab] - please read this policy before you post. Comments should be used for scholarly discussion of the content in question. You can find more information about how to use the commenting feature here [opens in a new tab] .
This site is protected by reCAPTCHA and the Google Privacy Policy [opens in a new tab] and Terms of Service [opens in a new tab] apply.