Novel Hypoxia Directed Cancer Therapeutics
Technical Report,01 Jul 2016,30 Jun 2018
Sanford Burnham Prebys Medical Discovery Institute La Jolla United States
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The hypoxia-inducible factors HIFs are proteins that have remained largely unexplored as possible targets for cancer therapeutics yet there is widespread recognition these proteins directly contribute to the progression of many types of human solid tumors. Having previously discovered that the HIF proteins contain small-molecule binding pockets within their architectures, we sought to identify small-molecules that bind and act directly through the HIF proteins to block their functions. Over the first year of funding, we produced large quantities of highly pure HIF proteins both HIF-1alphaARNT and HIF-2alphaARNT and used these proteins for conducting high-throughput screens with 32,000 different small-molecules. The screen was efficient and a mass-spectrometry based assay, and the hits obtained were further confirmed by a counter screen using another protein unrelated to HIFs. To understand the relative binding affinities of the hits, we carried out a biochemical assay to measure the equilibrium dissociation constants of the small molecules in binding to the HIF complexes. Over the coming year, we plan to examine these small-molecules in a number of cell-based studies to identify which ones are potent inhibitors that may be useful as possible use as anti-cancer therapies.
- Medicine and Medical Research