4WZ8

Crystal structure of human-yeast chimera acetyl coA carboxylase CT domain bound to Compound 6

4WZ8 の概要

• エントリーDOI: 10.2210/pdb4wz8/pdb
• 関連するPDBエントリー: 4WYO
• 分子名称: Acetyl-CoA carboxylase, 1'-(2H-indazol-5-ylcarbonyl)-1-(propan-2-yl)-1,4-dihydrospiro[indazole-5,4'-piperidin]-7(6H)-one (3 entities in total)
• 機能のキーワード: acc, acetyl-coa, ligase-ligase inhibitor complex, ligase/ligase inhibitor
• 由来する生物種: Saccharomyces cerevisiae (Baker's yeast)
• 細胞内の位置: Cytoplasm: Q00955
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 175224.62

構造登録者

Vajdos, F.F. (登録日: 2014-11-18, 公開日: 2014-12-10, 最終更新日: 2024-02-28)

主引用文献

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

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

実験手法

X-RAY DIFFRACTION (2.23 Å)