4mpc

Publication Abstract from PubMed

Pyruvate dehydrogenase kinase isoforms (PDKs 1 - 4) negatively regulate activity of the mitochondrial pyruvate dehydrogenase complex (PDC) by reversible phosphorylation. PDK isoforms are up-regulated in obesity, diabetes, heart failure and cancer and are potential therapeutic targets for these important human diseases. Here, we employed structure-guided design to convert a known Hsp90 inhibitor to a series of highly specific PDK inhibitors, based on structural conservation in the ATP-binding pocket. The key step involved the substitution of a carbonyl group in the parent compound with a sulfonyl in the PDK inhibitors. The final compound of this series, 2-[(2,4-dihydroxyphenyl)sulfonyl] isoindoline-4,6-diol, designated PS10, inhibits all four PDK isoforms with IC50 = 0.8 muM for PDK2. The administration of PS10 (70 mg/kg) to diet-induced obese mice significantly augments PDC activity with reduced phosphorylation in different tissues. Prolonged PS10 treatments result in improved glucose tolerance and notably lessened hepatic steatosis in the mouse model. The results support the pharmacological approach of targeting PDK to control both glucose and fat levels in obesity and type 2 diabetes.

Structure-guided Development of Specific Pyruvate Dehydrogenase Kinase Inhibitors Targeting the ATP-binding Pocket.,Tso SC, Qi X, Gui WJ, Wu CY, Chuang JL, Wernstedt-Asterholm I, Morlock LK, Owens KR, Scherer PE, Williams NS, Tambar UK, Wynn RM, Chuang DT J Biol Chem. 2013 Dec 19. PMID:24356970^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.