生物活性

• 描述Hypoxia-inducible factor (HIF)-1α/β heterodimer binds to the hypoxia-response element (HRE) to induce the transcription of genes related to angiogenesis, metastasis, and resistance in human cancers. IDF-11774 reduced the HRE-luciferase activity of HIF-1α with an IC₅₀ value of 3.65 μM. It also inhibited the accumulation of HIF-1α accumulation under hypoxic conditions in HCT116 human colon cancer cells at the doses of 5-20 μM. Treatment of human umbilical vascular endothelial cells with 20 μM IDF-11774 resulted in a reduction of capillary network formation on Matrigel as compared to DMSO-treated controls. IDF-11774 at 20 μM also decreased the mRNA expression of GLUT1 and pyruvate dehydrogenase kinase, and suppressed the cellular uptake of [³H]2-deoxyglucose in HCT116 cells. Twelve-hour treatment with 10 μM IDF-11774 significantly reduced the levels of intracellular lactate, NAD⁺ and NADP⁺. In mice inoculated with HCT116 cells, daily oral administration of IDF-11774 (10, 30, or 60 mg/kg/day) for two weeks significantly inhibited tumor growth at a dose-dependent manner in comparison to vehicle-treated controls. Mechanism: IDF-11774 is a novel HIF-1 inhibitor that suppresses the accumulation of HIF-1α both in vitro and in vivo.