2ydk

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[[Image:2ydk.png|left|200px]]
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==Discovery of Checkpoint Kinase Inhibitor AZD7762 by Structure Based Design and Optimization of Thiophene Carboxamide Ureas==
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<StructureSection load='2ydk' size='340' side='right' caption='[[2ydk]], [[Resolution|resolution]] 1.90&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[2ydk]] is a 1 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=2YDK OCA]. <br>
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</td></tr><tr><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=YDK:2-(CARBAMOYLAMINO)-5-PHENYL-N-[(3S)-PIPERIDIN-3-YL]THIOPHENE-3-CARBOXAMIDE'>YDK</scene><br>
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<tr><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2xf0|2xf0]], [[2brb|2brb]], [[2x8d|2x8d]], [[2wmr|2wmr]], [[2cgv|2cgv]], [[2brn|2brn]], [[2wmx|2wmx]], [[2ayp|2ayp]], [[2cgu|2cgu]], [[1nvs|1nvs]], [[2brm|2brm]], [[1nvq|1nvq]], [[2wmt|2wmt]], [[2ydi|2ydi]], [[2cgx|2cgx]], [[2c3j|2c3j]], [[2bro|2bro]], [[2wmw|2wmw]], [[2wmu|2wmu]], [[2brh|2brh]], [[2x8e|2x8e]], [[2c3k|2c3k]], [[1nvr|1nvr]], [[2wmq|2wmq]], [[1zlt|1zlt]], [[2cgw|2cgw]], [[2xez|2xez]], [[1zys|1zys]], [[1ia8|1ia8]], [[2br1|2br1]], [[2brg|2brg]], [[2wmv|2wmv]], [[2wms|2wms]], [[2c3l|2c3l]], [[2x8i|2x8i]], [[2xey|2xey]], [[2ydj|2ydj]]</td></tr>
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<tr><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Glucokinase Glucokinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.1.2 2.7.1.2] </span></td></tr>
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<tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2ydk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2ydk OCA], [http://www.rcsb.org/pdb/explore.do?structureId=2ydk RCSB], [http://www.ebi.ac.uk/pdbsum/2ydk PDBsum]</span></td></tr>
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<table>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Checkpoint kinases, CHK1 and CHK2 are activated in response to DNA damage that results in cell cycle arrest allowing sufficient time for DNA repair. Agents which lead to abrogation of such checkpoints have potential to increase the efficacy of such as chemo- and radio-therapies. Thiophene carboxamide ureas (TCUs) were identified as inhibitors of CHK1 by high throughput screening. A structure-based approach is described using crystal structures of JNK1 and CHK1 in complex with 1 and 2, and of the CHK1-3b complex. The ribose binding pocket of CHK1 was targetted to generate inhibitors with excellent cellular potency and selectivity over CDK1and IKKbeta key features lacking from the initial compounds. Optimization of 3b resulted in the identification of a regioisomeric 3-TCU lead, 12a. Optimization of 12a led to the discovery of the clinical candidate 4 (AZD7762), that strongly potentiates the efficacy of a variety of DNA-damaging agents in preclinical models.
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{{STRUCTURE_2ydk| PDB=2ydk | SCENE= }}
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Discovery of Checkpoint Kinase Inhibitor (S)-5-(3-fluorophenyl)-N-(piperidin-3-yl)-3-ureidothiophene-2-carboxamide (AZD7762) by Structure Based Design and Optimization of Thiophene Carboxamide Ureas.,Oza VB, Ashwell S, Almeida L, Brassil P, Breed J, Deng C, Gero T, Grondine M, Horn C, Ioannidis S, Liu D, Lyne PD, Newcombe N, Pass M, Read J, Ready S, Rowsell S, Su M, Toader D, Vasbinder M, Yu D, Yu Y, Xue Y, Zabludoff S, Janetka J J Med Chem. 2012 May 2. PMID:22551018<ref>PMID:22551018</ref>
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===Discovery of Checkpoint Kinase Inhibitor AZD7762 by Structure Based Design and Optimization of Thiophene Carboxamide Ureas===
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
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</div>
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{{ABSTRACT_PUBMED_22551018}}
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== References ==
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<references/>
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==About this Structure==
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__TOC__
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[[2ydk]] is a 1 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=2YDK OCA].
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</StructureSection>
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==Reference==
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<ref group="xtra">PMID:022551018</ref><references group="xtra"/>
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[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Non-specific serine/threonine protein kinase]]
[[Category: Non-specific serine/threonine protein kinase]]

Revision as of 07:44, 14 May 2014

Discovery of Checkpoint Kinase Inhibitor AZD7762 by Structure Based Design and Optimization of Thiophene Carboxamide Ureas

2ydk, resolution 1.90Å

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