4q1f: Difference between revisions
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''' | ==Human dCK C4S-S74E mutant in complex with UDP and the inhibitor 12R {N-{2-[5-(4-{(1R)-1-[(4,6-diaminopyrimidin-2-yl)sulfanyl]ethyl}-5-methyl-1,3-thiazol-2-yl)-2-methoxyphenoxy]ethyl}methanesulfonamide}== | ||
<StructureSection load='4q1f' size='340' side='right' caption='[[4q1f]], [[Resolution|resolution]] 2.10Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4q1f]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4Q1F OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4Q1F FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=2XN:N-{2-[5-(4-{(1R)-1-[(4,6-DIAMINOPYRIMIDIN-2-YL)SULFANYL]ETHYL}-5-METHYL-1,3-THIAZOL-2-YL)-2-METHOXYPHENOXY]ETHYL}METHANESULFONAMIDE'>2XN</scene>, <scene name='pdbligand=UDP:URIDINE-5-DIPHOSPHATE'>UDP</scene></td></tr> | |||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4q18|4q18]], [[4q19|4q19]], [[4q1a|4q1a]], [[4q1b|4q1b]], [[4q1c|4q1c]], [[4q1d|4q1d]], [[4q1e|4q1e]]</td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Deoxycytidine_kinase Deoxycytidine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.1.74 2.7.1.74] </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=4q1f FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4q1f OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4q1f RCSB], [http://www.ebi.ac.uk/pdbsum/4q1f PDBsum]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Recently, we have shown that small molecule dCK inhibitors in combination with pharmacological perturbations of de novo dNTP biosynthetic pathways could eliminate acute lymphoblastic leukemia cells in animal models. However, our previous lead compound had a short half-life in vivo. Therefore, we set out to develop dCK inhibitors with favorable pharmacokinetic properties. We delineated the sites of the inhibitor for modification, guided by crystal structures of dCK in complex with the lead compound and with derivatives. Crystal structure of the complex between dCK and the racemic mixture of our new lead compound indicated that the R-isomer is responsible for kinase inhibition. This was corroborated by kinetic analysis of the purified enantiomers, which showed that the R-isomer has >60-fold higher affinity than the S-isomer for dCK. This new lead compound has significantly improved metabolic stability, making it a prime candidate for dCK-inhibitor based therapies against hematological malignancies and, potentially, other cancers. | |||
Structure-guided development of deoxycytidine kinase inhibitors with nanomolar affinity and improved metabolic stability.,Nomme J, Li Z, Gipson RM, Wang J, Armijo AL, Le T, Poddar S, Smith T, Santarsiero BD, Nguyen HA, Czernin J, Alexandrova AN, Jung ME, Radu CG, Lavie A J Med Chem. 2014 Oct 23. PMID:25341194<ref>PMID:25341194</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Deoxycytidine kinase]] | |||
[[Category: Lavie, A.]] | |||
[[Category: Nomme, J.]] | |||
[[Category: Deoxycytidine]] | |||
[[Category: Inhibitor complex]] | |||
[[Category: Kinase]] | |||
[[Category: Phosphoryl transfer]] | |||
[[Category: Phosphorylation]] | |||
[[Category: Transferase]] | |||
[[Category: Transferase-transferase inhibitor complex]] | |||
Revision as of 11:47, 5 November 2014
Human dCK C4S-S74E mutant in complex with UDP and the inhibitor 12R {N-{2-[5-(4-{(1R)-1-[(4,6-diaminopyrimidin-2-yl)sulfanyl]ethyl}-5-methyl-1,3-thiazol-2-yl)-2-methoxyphenoxy]ethyl}methanesulfonamide}
Structural highlights
Publication Abstract from PubMedRecently, we have shown that small molecule dCK inhibitors in combination with pharmacological perturbations of de novo dNTP biosynthetic pathways could eliminate acute lymphoblastic leukemia cells in animal models. However, our previous lead compound had a short half-life in vivo. Therefore, we set out to develop dCK inhibitors with favorable pharmacokinetic properties. We delineated the sites of the inhibitor for modification, guided by crystal structures of dCK in complex with the lead compound and with derivatives. Crystal structure of the complex between dCK and the racemic mixture of our new lead compound indicated that the R-isomer is responsible for kinase inhibition. This was corroborated by kinetic analysis of the purified enantiomers, which showed that the R-isomer has >60-fold higher affinity than the S-isomer for dCK. This new lead compound has significantly improved metabolic stability, making it a prime candidate for dCK-inhibitor based therapies against hematological malignancies and, potentially, other cancers. Structure-guided development of deoxycytidine kinase inhibitors with nanomolar affinity and improved metabolic stability.,Nomme J, Li Z, Gipson RM, Wang J, Armijo AL, Le T, Poddar S, Smith T, Santarsiero BD, Nguyen HA, Czernin J, Alexandrova AN, Jung ME, Radu CG, Lavie A J Med Chem. 2014 Oct 23. PMID:25341194[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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