The ultimate objective of Project 4 is aimed at the discovery of potent and specific synthetic organic compounds that inhibit hypoxia-mediated gene activation. The growth of many different types of human tumors has been found to critically rely on an evolutionarily conserved hypoxia response pathway. Research over the past decade has identified hypoxia induced factor (HIF), a heterodimeric member of the basichelix- loop-helix (bHLH) PAS domain family of transcription factors, as a central component of the pathway used by cells to adapt to conditions of low oxygen tension. Under normoxic conditions, the HIF-1 subunit is rapidly degraded by ubiquitin-dependent proteolysis via the product of the von Hipple Lindau tumor suppressor gene, a dedicated subunit of a multiprotein ubiquitin ligase complex. Hypoxia also leads to the activation of HIF transactivation domains, thus facilitating transcription of HIF-responsive genes. The products of this gene regulatory network include: (i) vascular endothelial growth factor (VEGF), a polypeptide growth factor that assists in the formation of neovascular tissue essential for the growth of oxygen-starved solid tumors; and (ii) a concerted group of metabolic enzymes that allow tumor cells to grow glycolytically. Both hypoxia-dependent and hypoxia-independent stabilization/activation of HIF facilitate the progression of a wide spectrum of human tumors. Two approaches will be employed to search for inhibitors of HIF.
Specific Aim 1 will employ a sensitive and biologically sound cell-based assay to undertake high throughput drug screening (HTS) in search of HIF inhibitors.
Specific Aim 2 will employ a more rational, NMR-based approach to search for HIF inhibitors. In concert, these two approaches offer unique and complementary approaches aimed at the identification of small molecule drugs that may offer an entirely novel means of impeding the growth of human tumors.
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