2gmx: Difference between revisions
New page: left|200px<br /> <applet load="2gmx" size="450" color="white" frame="true" align="right" spinBox="true" caption="2gmx, resolution 3.50Å" /> '''Selective Aminopyri... |
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[[Image:2gmx.gif|left|200px]]<br /> | [[Image:2gmx.gif|left|200px]]<br /><applet load="2gmx" size="350" color="white" frame="true" align="right" spinBox="true" | ||
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caption="2gmx, resolution 3.50Å" /> | caption="2gmx, resolution 3.50Å" /> | ||
'''Selective Aminopyridine-Based C-Jun N-terminal Kinase inhibitors with cellular activity'''<br /> | '''Selective Aminopyridine-Based C-Jun N-terminal Kinase inhibitors with cellular activity'''<br /> | ||
==Overview== | ==Overview== | ||
The c-Jun N-terminal kinases (JNK-1, -2, and -3) are members of the | The c-Jun N-terminal kinases (JNK-1, -2, and -3) are members of the mitogen activated protein (MAP) kinase family of enzymes. They are activated in response to certain cytokines, as well as by cellular stresses including chemotoxins, peroxides, and irradiation. They have been implicated in the pathology of a variety of different diseases with an inflammatory component including asthma, stroke, Alzheimer's disease, and type 2 diabetes mellitus. In this work, high-throughput screening identified a JNK inhibitor with an excellent kinase selectivity profile. Using X-ray crystallography and biochemical screening to guide our lead optimization, we prepared compounds with inhibitory potencies in the low-double-digit nanomolar range, activity in whole cells, and pharmacokinetics suitable for in vivo use. The new compounds were over 1,000-fold selective for JNK-1 and -2 over other MAP kinases including ERK2, p38alpha, and p38delta and showed little inhibitory activity against a panel of 74 kinases. | ||
==Disease== | ==Disease== | ||
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==About this Structure== | ==About this Structure== | ||
2GMX is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with SO4 and 877 as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Mitogen-activated_protein_kinase Mitogen-activated protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.24 2.7.11.24] Full crystallographic information is available from [http:// | 2GMX is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=SO4:'>SO4</scene> and <scene name='pdbligand=877:'>877</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Mitogen-activated_protein_kinase Mitogen-activated protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.24 2.7.11.24] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2GMX OCA]. | ||
==Reference== | ==Reference== | ||
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[[Category: protein kinase jnk1 inhibitors]] | [[Category: protein kinase jnk1 inhibitors]] | ||
''Page seeded by [http:// | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 17:33:17 2008'' | ||
Revision as of 18:33, 21 February 2008
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Selective Aminopyridine-Based C-Jun N-terminal Kinase inhibitors with cellular activity
OverviewOverview
The c-Jun N-terminal kinases (JNK-1, -2, and -3) are members of the mitogen activated protein (MAP) kinase family of enzymes. They are activated in response to certain cytokines, as well as by cellular stresses including chemotoxins, peroxides, and irradiation. They have been implicated in the pathology of a variety of different diseases with an inflammatory component including asthma, stroke, Alzheimer's disease, and type 2 diabetes mellitus. In this work, high-throughput screening identified a JNK inhibitor with an excellent kinase selectivity profile. Using X-ray crystallography and biochemical screening to guide our lead optimization, we prepared compounds with inhibitory potencies in the low-double-digit nanomolar range, activity in whole cells, and pharmacokinetics suitable for in vivo use. The new compounds were over 1,000-fold selective for JNK-1 and -2 over other MAP kinases including ERK2, p38alpha, and p38delta and showed little inhibitory activity against a panel of 74 kinases.
DiseaseDisease
Known diseases associated with this structure: Diabetes mellitus, noninsulin-dependent OMIM:[604641]
About this StructureAbout this Structure
2GMX is a Protein complex structure of sequences from Homo sapiens with and as ligands. Active as Mitogen-activated protein kinase, with EC number 2.7.11.24 Full crystallographic information is available from OCA.
ReferenceReference
Aminopyridine-based c-Jun N-terminal kinase inhibitors with cellular activity and minimal cross-kinase activity., Szczepankiewicz BG, Kosogof C, Nelson LT, Liu G, Liu B, Zhao H, Serby MD, Xin Z, Liu M, Gum RJ, Haasch DL, Wang S, Clampit JE, Johnson EF, Lubben TH, Stashko MA, Olejniczak ET, Sun C, Dorwin SA, Haskins K, Abad-Zapatero C, Fry EH, Hutchins CW, Sham HL, Rondinone CM, Trevillyan JM, J Med Chem. 2006 Jun 15;49(12):3563-80. PMID:16759099
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