Description
Hypoxia-inducible factor-
1 (HIF-
1) is a heterodimeric transcription factor composed of a HIF-
1α subunit and HIF-
1β subunit. Whereas the HIF-
1β subunit is constitutively expressed, the HIF-
1α subunit is regulated by cellular oxygen levels and therefore plays an important role in maintaining cellular oxygen homeostasis. Under normoxic conditions, HIF-
1α is selectively hydroxylated on proline residues 402 and 577 and targeted for destruction by the ubiquitin-
proteasome system. Under hypoxic conditions, HIF-
1α accumulates and dimerizes with HIF-
1β to promote the transcription of a number of genes involved in angiogenesis, glycolysis, growth factor signaling, tumor invasion, and metastasis. CAY10585 is a novel small molecule inhibitor of HIF-
1α accumulation and gene transcriptional activity. In a gene reporter assay using human Hep3B and AGS cell lines, CAY10585 prevented HIF-
1 transcriptional activity with IC
50 values of 2.6 and 0.7 μM, respectively. It blocks HIF-
1α accumulation in Hep3B cells in a concentration and time-
dependent manner, with complete inhibition at a concentration of 30 μM within 12 hours. CAY10585 also significantly suppresses transcription of the HIF-
1 target genes VEGF and erythropoietin at 10 μM.
