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 IC50 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.
