The Hypoxia Inducible transcription Factors (HIFs) are induced in a large number of cancers where theyupregulate the expression of over 100 genes, many of which are expected to promote tumor progression andconfer resistance to traditional therapies. The goals of Project 4 are the elucidation and validation of targetsfor the discovery of small molecules that modulate this response with the objective of using these reagents toassess the contribution of HIF to tumorigenesis in in vivo model systems. Biologically sound cell-based highthroughput screens exploiting knowledge of oxygen-dependent modes of HIF regulation have led to theidentification of both siRNAs and potent (nanomolar) small molecules that either antagonize or agonize thepathway. Though the molecular targets for some of these agents have been successfully identified, Aim 1proposes biochemical, molecular biological and genetic approaches to pursue the modes-of-action of theremaining compounds as their targets may represent unidentified components of the hypoxic responsepathway. Concurrently, structural, biochemical, and biological approaches have rigorously characterized theHIF Per-ARNT-Sim (PAS) domains responsible for mediating interactions between subunits of the HIFheterodimer.
Aim 2 extends these studies to investigate a working model for HIF assembly. Using suchinformation, proof-of-principle ligands for these PAS domains have been identified and shown to function asallosteric inhibitors of HIF heterodimerization in vitro and provide justification for the development of new,high throughput, assays for future screens. Furthermore, the best compounds from each Aim will besubjected to systematic chemical efforts to improve their potency, stability, and solubility for use in studies tointerrogate their efficacy in in vivo models of human diseases. These complementary routes offer uniqueopportunities to gain insight into HIF function and mechanisms by which it may be artificially regulated.Relevance to public health: Increased levels of HIF are observed in several human tumors and correlatedwith tumor aggressiveness, resistance to treatment and mortality. In addition, HIF is induced in severaldiseases in which oxygen availability is compromised, including anemias and ischemias. As such, smallmolecule modulation of HIF activity may have therapeutic utility in a range of diseases including cancer.
Showing the most recent 10 out of 67 publications
