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4WYO

Crystal structure of human-yeast chimera acetyl coA carboxylase CT domain bound to Compound 1

Summary for 4WYO
Entry DOI10.2210/pdb4wyo/pdb
Related4WZ8
DescriptorAcetyl-CoA carboxylase, 2'-tert-butyl-1-(2H-indazol-5-ylcarbonyl)-2'H-spiro[piperidine-4,5'-pyrano[3,2-c]pyrazol]-7'(6'H)-one (3 entities in total)
Functional Keywordsacc, acetyl-coa, ligase-ligase inhibitor complex, ligase/ligase inhibitor
Biological sourceSaccharomyces cerevisiae (Baker's yeast)
Cellular locationCytoplasm: Q00955
Total number of polymer chains2
Total formula weight175256.62
Authors
Vajdos, F.F. (deposition date: 2014-11-17, release date: 2015-01-14, Last modification date: 2024-02-28)
Primary citationGriffith, D.A.,Kung, D.W.,Esler, W.P.,Amor, P.A.,Bagley, S.W.,Beysen, C.,Carvajal-Gonzalez, S.,Doran, S.D.,Limberakis, C.,Mathiowetz, A.M.,McPherson, K.,Price, D.A.,Ravussin, E.,Sonnenberg, G.E.,Southers, J.A.,Sweet, L.J.,Turner, S.M.,Vajdos, F.F.
Decreasing the Rate of Metabolic Ketone Reduction in the Discovery of a Clinical Acetyl-CoA Carboxylase Inhibitor for the Treatment of Diabetes.
J.Med.Chem., 57:10512-10526, 2014
Cited by
PubMed Abstract: 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.
PubMed: 25423286
DOI: 10.1021/jm5016022
PDB entries with the same primary citation
Experimental method
X-RAY DIFFRACTION (2.89 Å)
Structure validation

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