4wz8
From Proteopedia
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| - | ''' | + | ==Crystal structure of human-yeast chimera acetyl coA carboxylase CT domain bound to Compound 6== |
| + | <StructureSection load='4wz8' size='340' side='right' caption='[[4wz8]], [[Resolution|resolution]] 2.23Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[4wz8]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4WZ8 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4WZ8 FirstGlance]. <br> | ||
| + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=3W7:1-(2H-INDAZOL-5-YLCARBONYL)-1-(PROPAN-2-YL)-1,4-DIHYDROSPIRO[INDAZOLE-5,4-PIPERIDIN]-7(6H)-ONE'>3W7</scene></td></tr> | ||
| + | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4wyo|4wyo]]</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=4wz8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4wz8 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4wz8 RCSB], [http://www.ebi.ac.uk/pdbsum/4wz8 PDBsum]</span></td></tr> | ||
| + | </table> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Acetyl-CoA carboxylase (ACC) inhibitors offer significant potential for the treatment of type 2 diabetes mellitus (T2DM), hepatic steatosis, and cancer. However, the identification of tool compounds suitable to test the hypothesis in human trials has been challenging. An advanced series of spirocyclic ketone-containing ACC inhibitors recently reported by Pfizer were metabolized in vivo by ketone reduction which complicated human pharmacology projections. We disclose that this metabolic reduction can be greatly attenuated through introduction of steric hindrance adjacent to the ketone carbonyl. Incorporation of weakly-basic functionality improved solubility and led to the identification of 9 as a clinical candidate for the treatment of T2DM. Phase I clinical studies demonstrated dose-proportional increases in exposure, single-dose inhibition of de novo lipogenesis (DNL), and changes in indirect calorimetry consistent with increased whole-body fatty acid oxidation. This demonstration of target engagement validates the use of compound 9 to evaluate the role of DNL in human disease. | ||
| - | + | Decreasing the Rate of Metabolic Ketone Reduction in the Discovery of a Clinical Acetyl-CoA Carboxylase Inhibitor for the Treatment of Diabetes.,Griffith DA, Kung DW, Esler WP, Amor PA, Bagley SW, Beysen C, Carvajal-Gonzalez S, Doran SD, Limberakis C, Mathiowetz AM, McPherson RK, Price DA, Ravussin E, Sonnenberg GE, Southers JA, Sweet LJ, Turner SM, Vajdos FF J Med Chem. 2014 Nov 25. PMID:25423286<ref>PMID:25423286</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | + | </div> | |
| - | + | == References == | |
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Vajdos, F F]] | ||
| + | [[Category: Acc]] | ||
| + | [[Category: Acetyl-coa]] | ||
| + | [[Category: Ligase-ligase inhibitor complex]] | ||
Revision as of 16:03, 10 December 2014
Crystal structure of human-yeast chimera acetyl coA carboxylase CT domain bound to Compound 6
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