TITLE: Treatment of Type 2 Diabetes, Cancer and Heart Failure by Inhibiting all four
Mitochondrial Pyruvate Dehydrogenase Isoforms
INVENTORS: David Chuang
TECHNOLOGY: Biologicals
UTSD: 2719
SUMMARY: 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. We sought to develop robust PDK inhibitors that can be used to improve glucose metabolism and correct metabolic dysfunction in vivo . Based on the unique structural features present in the ATP-binding pocket of PDK2, a single functional group change was made in a known Hsp90 inhibitor that binds to the corresponding pocket of the latter protein from the GHKL family. This approach efficiently converted the Hsp90 inhibitor to a highly specific inhibitor for all PDK isoforms. The final PDK inhibitors of this series robustly augments PDC activity with reduced phosphorylation in tissues, which leads to improved glucose tolerance and reduced hepatic steatosis in diet-induced obese (DIO) mice. These findings demonstrate the utility of structure-based inhibitor design and support the pharmacological approach of targeting PDK to control glucose and fat levels in obesity and type 2 diabetes.
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Please reference UT Southwestern Case Number: 2719