4qyh: Difference between revisions
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''' | ==CHK1 kinase domain in complex with diazacarbazole GNE-783== | ||
<StructureSection load='4qyh' size='340' side='right' caption='[[4qyh]], [[Resolution|resolution]] 1.90Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4qyh]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4QYH OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4QYH FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=3DX:3-[4-(4-METHYLPIPERAZIN-1-YL)PHENYL]-9H-PYRROLO[2,3-B 5,4-C]DIPYRIDINE-6-CARBONITRILE'>3DX</scene></td></tr> | |||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4qye|4qye]], [[4qyf|4qyf]], [[4qyg|4qyg]]</td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1] </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=4qyh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4qyh OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4qyh RCSB], [http://www.ebi.ac.uk/pdbsum/4qyh PDBsum]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Checkpoint kinase 1 (ChK1) is activated in response to DNA damage, acting to temporarily block cell cycle progression and allow for DNA repair. It is envisaged that inhibition of ChK1 will sensitize tumor cells to treatment with DNA-damaging therapies, and may enhance the therapeutic window. High throughput screening identified carboxylate-containing diarylpyrazines as a prominent hit series, but with limited biochemical potency and no cellular activity. Through a series of SAR investigations and X-ray crystallographic analysis the critical role of polar contacts with conserved waters in the kinase back pocket was established. Structure-based design, guided by in silico modeling, transformed the series to better satisfy these contacts and the novel 1,7-diazacarbazole class of inhibitors was discovered. Here we present the genesis of this novel series and the identification of GNE-783, a potent, selective and orally bioavailable inhibitor of ChK1. | |||
Discovery of the 1,7-diazacarbazole class of inhibitors of checkpoint kinase 1.,Gazzard L, Appleton B, Chapman K, Chen H, Clark K, Drobnick J, Goodacre S, Halladay J, Lyssikatos J, Schmidt S, Sideris S, Wiesmann C, Williams K, Wu P, Yen I, Malek S Bioorg Med Chem Lett. 2014 Dec 15;24(24):5704-9. doi: 10.1016/j.bmcl.2014.10.063., Epub 2014 Oct 27. PMID:25453805<ref>PMID:25453805</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Non-specific serine/threonine protein kinase]] | |||
[[Category: Wiesmann, C]] | |||
[[Category: Wu, P]] | |||
[[Category: Phosphotransfer catalyst]] | |||
[[Category: Protein kinase]] | |||
[[Category: Transferase-transferase inhibitor complex]] | |||
Revision as of 15:46, 17 December 2014
CHK1 kinase domain in complex with diazacarbazole GNE-783CHK1 kinase domain in complex with diazacarbazole GNE-783
Structural highlights
Publication Abstract from PubMedCheckpoint kinase 1 (ChK1) is activated in response to DNA damage, acting to temporarily block cell cycle progression and allow for DNA repair. It is envisaged that inhibition of ChK1 will sensitize tumor cells to treatment with DNA-damaging therapies, and may enhance the therapeutic window. High throughput screening identified carboxylate-containing diarylpyrazines as a prominent hit series, but with limited biochemical potency and no cellular activity. Through a series of SAR investigations and X-ray crystallographic analysis the critical role of polar contacts with conserved waters in the kinase back pocket was established. Structure-based design, guided by in silico modeling, transformed the series to better satisfy these contacts and the novel 1,7-diazacarbazole class of inhibitors was discovered. Here we present the genesis of this novel series and the identification of GNE-783, a potent, selective and orally bioavailable inhibitor of ChK1. Discovery of the 1,7-diazacarbazole class of inhibitors of checkpoint kinase 1.,Gazzard L, Appleton B, Chapman K, Chen H, Clark K, Drobnick J, Goodacre S, Halladay J, Lyssikatos J, Schmidt S, Sideris S, Wiesmann C, Williams K, Wu P, Yen I, Malek S Bioorg Med Chem Lett. 2014 Dec 15;24(24):5704-9. doi: 10.1016/j.bmcl.2014.10.063., Epub 2014 Oct 27. PMID:25453805[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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