University of Texas System

Richard Keith Bruick

Steven L McKnight

Charles G Caldwell

Doug E Frantz

Kevin H Gardner

John B MacMillan

Uttam K Tambar

Yaomin Chen

Thomas H Scheuermann

Julio Cesar Francisco Ruiz

The present disclosure relates to HIF-2&#x3b1; inhibitors and methods of making and using them for treating iron overload disorders. Certain compounds were potent in HIF-2&#x3b1; scintillation proximity assay, luciferase assay, and VEGF ELISA assay, and reduced liver iron accumulation and serum iron parameters in both prophylactic and treatment mouse models.

HIF-2&#x3b1; inhibitors for treating iron overload disorders

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)

The invention provides methods and compositions for assaying hypoxia-inducible factor (HIF) prolyl hydroxylation. Subject assays may be cell-based or in vitro, and comprise incubating a mixture comprising an isolated or recombinantly expressed HIF-specific prolyl hydroxylase (HPH), and a substrate of the hydroxylase, under conditions whereby the hydroxylase prolyl hydroxylates the substrate, and detecting a resultant prolyl hydroxylation of the substrate. The mixture may also comprise a candidate agent which modulates the resultant prolyl hydroxylation. In particular embodiments, the hydroxylase is selected from the group consisting of human HPH1, HPH2 and HPH3, and/or the substrate comprises LAPY, wherein P is hydroxylated by the hydroxylase.

Prolyl-4-hydroxylases

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Dallas, TX, United States of America

Richard Keith Bruick