2p55: Difference between revisions

Revision as of 19:26, 21 February 2008

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

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 with , and as ligands. Active as Mitogen-activated protein kinase kinase, with EC number 2.7.12.2 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

Page seeded by OCA on Thu Feb 21 18:26:00 2008

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

OCA

@@ Line 4: / Line 4: @@
 ==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.
+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 Structure==
@@ Line 10: / Line 10: @@
 ==Reference==
--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:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=17880056 17880056]
+-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:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=17880056 17880056]
 [[Category: Homo sapiens]]
 [[Category: Mitogen-activated protein kinase kinase]]
 [[Category: Single protein]]
-[[Category: Ohren, J.F.]]
+[[Category: Ohren, J F.]]
-[[Category: Pavlovsky, A.G.]]
+[[Category: Pavlovsky, A G.]]
 [[Category: ATP]]
 [[Category: MG]]
@@ Line 24: / Line 24: @@
 [[Category: transferase]]
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Jan 23 12:04:38 2008''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 18:26:00 2008''