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Description

A cell-permeable, metabolically stable (t1/2 = 14 h in 786-0 cultures, no metabolization up to 24 h in medium alone), non-cytotoxic (up to 30 µ,M & 24 h in 786-0 and Hep3B cultures) benzoxadiazolamine that prevents HIF-2alpha-HIF-beta/ARNT (aryl hydrocarbon receptor nuclear translocator) heterodimeration by perturbing HIF-2alpha Per-ARNT-Sim/PAS-B domain surface beta-sheet conformation via a 1:1 stoichiometric binding to HIF-2alpha PAS-B internal cavity (KD = 81 nM), while exhibiting no affinity toward HIF-1alpha PAS-B domain (KD >>5 µ,M). Shown to inhibit nuclear HIF-2alpha-ARNT, but not HIF-1alpha-ARNT, association in hypoxic Hep3B cells in a dose-dependent manner (0.1 to 10 µ,M) and selectively decrease hypoxia-induced HIF-2alpha DNA binding and HIF-2alpha-dependent EPO mRNA upregulation (% inhibition/time/dose = 60%/6 h/1 µ,M, 90%/6 h/10 µ,M, 45%/12 h/1 µ,M, 93%/12 h/10 µ,M), displaying little effect toward HIF-1alpha DNA binding or HIF-1alpha-dependent PGK1 mRNA upregulation. Unlike HIF Inhibitors I-VI, this compound does not affect the cellular protein or mRNA levels of HIF-1alpha & HIF-2alpha., A cell-permeable benzoxadiazolamine that prevents HIF-2alpha-HIF-beta/ARNT heterodimeration by perturbing HIF-2alpha Per-ARNT-Sim/PAS-B domain surface beta-sheet conformation via a 1:1 stoichiometric binding (KD = 81 nM), while exhibiting no affinity toward HIF-1alphaPAS-B domain. Shown to be metabolically stable and non-cytotoxic in cultures and selectively inhibit hypoxia-induced HIF-2alpha DNA binding and HIF-2alpha-dependent EPO mRNA upregulation (1 to10 µ,M for 6 to 12 h), but not HIF-1alpha DNA binding or HIF-1alpha-dependent PGK1 mRNA upregulation, in Hep3B cells. Unlike HIF Inhibitors I-VI, this compound does not affect the cellular protein or mRNA levels of HIF-1alpha & HIF-2alpha.