2p55
X-ray structure of the human mitogen-activated protein kinase kinase 1 (MEK1) in a complex with ligand and MgATP
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| , resolution 2.8Å | |||||||
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| Ligands: | , and | ||||||
| Gene: | MAP2K1, MEK1, PRKMK1 (Homo sapiens) | ||||||
| Activity: | Mitogen-activated protein kinase kinase, with EC number 2.7.12.2 | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
OverviewOverview
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 suppression 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 StructureAbout this Structure
2P55 is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
ReferenceReference
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 Oct 18;50(21):5090-102. Epub 2007 Sep 19. PMID:17880056
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