Structure-guided development of specific pyruvate dehydrogenase kinase inhibitors targeting the ATP-binding pocket.
J Biol Chem
; 289(7): 4432-43, 2014 Feb 14.
Article
em En
| MEDLINE
| ID: mdl-24356970
ABSTRACT
Pyruvate dehydrogenase kinase isoforms (PDKs 1-4) negatively regulate activity of the mitochondrial pyruvate dehydrogenase complex 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 a 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 µM for PDK2. The administration of PS10 (70 mg/kg) to diet-induced obese mice significantly augments pyruvate dehydrogenase complex 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.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Sulfonas
/
Proteínas Serina-Treonina Quinases
/
Diabetes Mellitus Tipo 2
/
Inibidores Enzimáticos
/
Isoindóis
/
Fígado Gorduroso
/
Obesidade
Limite:
Animals
/
Humans
/
Male
Idioma:
En
Ano de publicação:
2014
Tipo de documento:
Article