Identification of a novel small-molecule inhibitor of the hypoxia-inducible factor 1 pathway

Academic Article


  • Hypoxia-inducible factor 1 (HIF-1) is the central mediator of cellular responses to low oxygen and has recently become an important therapeutic target for solid tumor therapy. Inhibition of HIF-1 is expected to result in the attenuation of hypoxia-inducible genes, which are vital to many aspects of tumor biology, including adaptative responses for survival under anaerobic conditions. To identify small molecules inhibiting the HIF-1 pathway, we did a biological screen on a 10,000-membered natural product-like combinatorial library. The compounds of the library, which share a 2,2-dimethylbenzopyran structural motif, were tested for their ability to inhibit the hypoxic activation of an alkaline phosphatase reporter gene under the control of hypoxia-responsive elements in human glioma cells. This effort led to the discovery of 103D5R, a novel small-molecule inhibitor of HIF-1α. 103D5R markedly decreased HIF-1α protein levels induced by hypoxia or cobaltous ions in a dose- and time-dependent manner, whereas minimally affecting global cellular protein expression levels, including that of control proteins such as HIF-1β, IκBα, and β-actin. The inhibitory activity of 103D5R against HIF-1α was clearly shown under normoxia and hypoxia in cells derived from different cancer types, including glioma, prostate, and breast cancers. This inhibition prevented the activation of HIF-1 target genes under hypoxia such as vascular endothelial growth factor (VEGF) and glucose transporter-1 (Glut-1). Investigations into the molecular mechanism showed that 103D5R strongly reduced HIF-1α protein synthesis, whereas HIF-1α mRNA levels and HIF-1α degradation were not affected. 103D5R inhibited the phosphorylation of Akt, Erk1/2, and stress-activated protein kinase/c-jun-NH2-kinase, without changing the total levels of these proteins. Further studies on the mechanism of action of 103D5R will likely provide new insights into its validity/applicability for the pharmacologic targeting of HIF-1α for therapeutic purposes.
  • Authors

    Published In

  • Cancer Research  Journal
  • Author List

  • Tan C; De Noronha RG; Roecker AJ; Pyrzynska B; Khwaja F; Zhang Z; Zhang H; Teng Q; Nicholson AC; Giannakakou P
  • Start Page

  • 605
  • End Page

  • 612
  • Volume

  • 65
  • Issue

  • 2