2p55

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spinqualitylabelsall models 2p55, resolution 2.8Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

X-ray structure of the human mitogen-activated protein kinase kinase 1 (MEK1) in a complex with ligand and MgATP

Overview

A new series of MEK1 inhibitors, the 4-anilino-5-carboxamido-2-pyridones, were designed and synthesized using a combination of medicinal chemistry, computational chemistry, and structural elucidation. The effect of, variation in the carboxamide side chain, substitution on the pyridone, nitrogen, and replacement of the 4'-iodide were all investigated. This, study afforded several compounds which were either equipotent or more, potent than the clinical candidate CI-1040 (1) in an isolated enzyme, assay, as well as murine colon carcinoma (C26) cells, as measured by, supression of phosphorylated ERK substrate. Most notably, pyridone 27 was, found to be more potent than 1 in vitro and produced a 100% response rate, at a lower dose than 1, when tested for in vivo efficacy in animals, bearing C26 tumors.

About this Structure

2P55 is a Single protein structure of sequence from Homo sapiens with MG, MRA and ATP as ligands. Active as Mitogen-activated protein kinase kinase, with EC number 2.7.12.2 Full crystallographic information is available from OCA.

Reference

4-Anilino-5-carboxamido-2-pyridone Derivatives as Noncompetitive Inhibitors of Mitogen-Activated Protein Kinase Kinase., Spicer JA, Rewcastle GW, Kaufman MD, Black SL, Plummer MS, Denny WA, Quin J 3rd, Shahripour AB, Barrett SD, Whitehead CE, Milbank JB, Ohren JF, Gowan RC, Omer C, Camp HS, Esmaeil N, Moore K, Sebolt-Leopold JS, Pryzbranowski S, Merriman RL, Ortwine DF, Warmus JS, Flamme CM, Pavlovsky AG, Tecle H, J Med Chem. 2007 Sep 19;. PMID:17880056

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