University of Texas System

Uttam K Tambar

Charles G Caldwell

Doug E Frantz

Kevin H Gardner

Richard Keith Bruick

Xiangbing Qi

John B MacMillan

R Max Wynn

David T Chuang

Wen-Jun Gui

Cheng-Yang Wu

Thomas H Scheuermann

Shih-Chia Tso

Jacinta L Chuang

The present disclosure relates to the identification of PDK inhibitors and their use in the treatment of diseases such as diabetes, cardiovascular disease and cancer. The invention relates to the development of 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. These final PDK inhibitors of this series robustly augments PDC activity with reduced phosphorylation in tissues.

Inhibitors of mitochondrial pyruvate dehydrogenase kinase isoforms 1-4 and uses thereof

Provided is a method of inhibiting heterodimerization of HIF-2&#x3b1; to HIF1&#x3b2; (ARNT) comprising binding certain small molecules to the HIF-2&#x3b1; PAS-B domain cavity but not to HIF1&#x3b1; and inhibiting HIF-2&#x3b1; heterodimerization to HIF1&#x3b2; (ARNT) but not inhibiting HIF1&#x3b1; heterodimerization to HIF1&#x3b2; (ARNT). Those certain small molecules are also referenced synonymously as HIF2-HDI and HIF2&#x3b1; heterodimerization inhibitors and also simply as certain small molecules.

Inhibition of HIF-2&#x3b1; heterodimerization with HIF1&#x3b2; (ARNT)

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Dallas, TX, United States of America

Uttam K Tambar