3oxi: Difference between revisions
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==Design and Synthesis of Disubstituted Thiophene and Thiazole Based Inhibitors of JNK for the Treatment of Neurodegenerative Diseases== | |||
<StructureSection load='3oxi' size='340' side='right' caption='[[3oxi]], [[Resolution|resolution]] 2.20Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[3oxi]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3OXI OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3OXI FirstGlance]. <br> | |||
==Disease== | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=SYY:METHYL+3-[(THIOPHEN-2-YLACETYL)AMINO]THIOPHENE-2-CARBOXYLATE'>SYY</scene></td></tr> | ||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">JNK3, JNK3A, MAPK10, PRKM10 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens]), MAPK8IP1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[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] </span></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3oxi FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3oxi OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3oxi RCSB], [http://www.ebi.ac.uk/pdbsum/3oxi PDBsum]</span></td></tr> | |||
</table> | |||
== Disease == | |||
[[http://www.uniprot.org/uniprot/MK10_HUMAN MK10_HUMAN]] Defects in MAPK10 are a cause of epileptic encephalopathy Lennox-Gastaut type (EELG) [MIM:[http://omim.org/entry/606369 606369]]. Epileptic encephalopathies of the Lennox-Gastaut group are childhood epileptic disorders characterized by severe psychomotor delay and seizures. Note=A chromosomal aberration involving MAPK10 has been found in a single patient. Translocation t(Y;4)(q11.2;q21) which causes MAPK10 truncation. | [[http://www.uniprot.org/uniprot/MK10_HUMAN MK10_HUMAN]] Defects in MAPK10 are a cause of epileptic encephalopathy Lennox-Gastaut type (EELG) [MIM:[http://omim.org/entry/606369 606369]]. Epileptic encephalopathies of the Lennox-Gastaut group are childhood epileptic disorders characterized by severe psychomotor delay and seizures. Note=A chromosomal aberration involving MAPK10 has been found in a single patient. Translocation t(Y;4)(q11.2;q21) which causes MAPK10 truncation. | ||
== Function == | |||
[[http://www.uniprot.org/uniprot/MK10_HUMAN MK10_HUMAN]] Serine/threonine-protein kinase involved in various processes such as neuronal proliferation, differentiation, migration and programmed cell death. Extracellular stimuli such as proinflammatory cytokines or physical stress stimulate the stress-activated protein kinase/c-Jun N-terminal kinase (SAP/JNK) signaling pathway. In this cascade, two dual specificity kinases MAP2K4/MKK4 and MAP2K7/MKK7 phosphorylate and activate MAPK10/JNK3. In turn, MAPK10/JNK3 phosphorylates a number of transcription factors, primarily components of AP-1 such as JUN and ATF2 and thus regulates AP-1 transcriptional activity. Plays regulatory roles in the signaling pathways during neuronal apoptosis. Phosphorylates the neuronal microtubule regulator STMN2. Acts in the regulation of the beta-amyloid precursor protein/APP signaling during neuronal differentiation by phosphorylating APP. Participates also in neurite growth in spiral ganglion neurons.<ref>PMID:11718727</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
From high throughput screening, we discovered compound 1, the prototype for a series of disubstituted thiophene inhibitors of JNK which is selective towards closely related MAP kinases p38 and Erk2. Herein we describe the evolution of these compounds to a novel class of thiophene and thiazole JNK inhibitors that retain favorable solubility, permeability, and P-gp properties for development as CNS agents for treatment of neurodegeneration. Compound 61 demonstrated JNK3 IC(50)=77 nM and retained the excellent broad kinase selectivity observed for the series. | |||
Design and synthesis of disubstituted thiophene and thiazole based inhibitors of JNK.,Hom RK, Bowers S, Sealy JM, Truong AP, Probst GD, Neitzel ML, Neitz RJ, Fang L, Brogley L, Wu J, Konradi AW, Sham HL, Toth G, Pan H, Yao N, Artis DR, Quinn K, Sauer JM, Powell K, Ren Z, Bard F, Yednock TA, Griswold-Prenner I Bioorg Med Chem Lett. 2010 Dec 15;20(24):7303-7. Epub 2010 Oct 21. PMID:21071223<ref>PMID:21071223</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
==See Also== | ==See Also== | ||
*[[Mitogen-activated protein kinase|Mitogen-activated protein kinase]] | *[[Mitogen-activated protein kinase|Mitogen-activated protein kinase]] | ||
== References == | |||
== | <references/> | ||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Mitogen-activated protein kinase]] | [[Category: Mitogen-activated protein kinase]] | ||
[[Category: Artis, D R | [[Category: Artis, D R]] | ||
[[Category: Bowers, S | [[Category: Bowers, S]] | ||
[[Category: Brogley, L | [[Category: Brogley, L]] | ||
[[Category: Fang, L | [[Category: Fang, L]] | ||
[[Category: Hom, R K | [[Category: Hom, R K]] | ||
[[Category: Konradi, A W | [[Category: Konradi, A W]] | ||
[[Category: Neitz, J | [[Category: Neitz, J]] | ||
[[Category: Neitzel, M | [[Category: Neitzel, M]] | ||
[[Category: Pan, H | [[Category: Pan, H]] | ||
[[Category: Probst, G D | [[Category: Probst, G D]] | ||
[[Category: Sealy, J | [[Category: Sealy, J]] | ||
[[Category: Sham, H | [[Category: Sham, H]] | ||
[[Category: Toth, G | [[Category: Toth, G]] | ||
[[Category: Truong, A | [[Category: Truong, A]] | ||
[[Category: Wu, J | [[Category: Wu, J]] | ||
[[Category: Yao, N | [[Category: Yao, N]] | ||
[[Category: Jnk inhibitor]] | [[Category: Jnk inhibitor]] | ||
[[Category: Kinase]] | [[Category: Kinase]] | ||
Revision as of 09:51, 19 December 2014
Design and Synthesis of Disubstituted Thiophene and Thiazole Based Inhibitors of JNK for the Treatment of Neurodegenerative DiseasesDesign and Synthesis of Disubstituted Thiophene and Thiazole Based Inhibitors of JNK for the Treatment of Neurodegenerative Diseases
Structural highlights
Disease[MK10_HUMAN] Defects in MAPK10 are a cause of epileptic encephalopathy Lennox-Gastaut type (EELG) [MIM:606369]. Epileptic encephalopathies of the Lennox-Gastaut group are childhood epileptic disorders characterized by severe psychomotor delay and seizures. Note=A chromosomal aberration involving MAPK10 has been found in a single patient. Translocation t(Y;4)(q11.2;q21) which causes MAPK10 truncation. Function[MK10_HUMAN] Serine/threonine-protein kinase involved in various processes such as neuronal proliferation, differentiation, migration and programmed cell death. Extracellular stimuli such as proinflammatory cytokines or physical stress stimulate the stress-activated protein kinase/c-Jun N-terminal kinase (SAP/JNK) signaling pathway. In this cascade, two dual specificity kinases MAP2K4/MKK4 and MAP2K7/MKK7 phosphorylate and activate MAPK10/JNK3. In turn, MAPK10/JNK3 phosphorylates a number of transcription factors, primarily components of AP-1 such as JUN and ATF2 and thus regulates AP-1 transcriptional activity. Plays regulatory roles in the signaling pathways during neuronal apoptosis. Phosphorylates the neuronal microtubule regulator STMN2. Acts in the regulation of the beta-amyloid precursor protein/APP signaling during neuronal differentiation by phosphorylating APP. Participates also in neurite growth in spiral ganglion neurons.[1] Publication Abstract from PubMedFrom high throughput screening, we discovered compound 1, the prototype for a series of disubstituted thiophene inhibitors of JNK which is selective towards closely related MAP kinases p38 and Erk2. Herein we describe the evolution of these compounds to a novel class of thiophene and thiazole JNK inhibitors that retain favorable solubility, permeability, and P-gp properties for development as CNS agents for treatment of neurodegeneration. Compound 61 demonstrated JNK3 IC(50)=77 nM and retained the excellent broad kinase selectivity observed for the series. Design and synthesis of disubstituted thiophene and thiazole based inhibitors of JNK.,Hom RK, Bowers S, Sealy JM, Truong AP, Probst GD, Neitzel ML, Neitz RJ, Fang L, Brogley L, Wu J, Konradi AW, Sham HL, Toth G, Pan H, Yao N, Artis DR, Quinn K, Sauer JM, Powell K, Ren Z, Bard F, Yednock TA, Griswold-Prenner I Bioorg Med Chem Lett. 2010 Dec 15;20(24):7303-7. Epub 2010 Oct 21. PMID:21071223[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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