4WYO
Crystal structure of human-yeast chimera acetyl coA carboxylase CT domain bound to Compound 1
Summary for 4WYO
| Entry DOI | 10.2210/pdb4wyo/pdb |
| Related | 4WZ8 |
| Descriptor | Acetyl-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 Keywords | acc, acetyl-coa, ligase-ligase inhibitor complex, ligase/ligase inhibitor |
| Biological source | Saccharomyces cerevisiae (Baker's yeast) |
| Cellular location | Cytoplasm: Q00955 |
| Total number of polymer chains | 2 |
| Total formula weight | 175256.62 |
| Authors | Vajdos, F.F. (deposition date: 2014-11-17, release date: 2015-01-14, Last modification date: 2024-02-28) |
| Primary citation | Griffith, 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: 25423286DOI: 10.1021/jm5016022 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.89 Å) |
Structure validation
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