Novel Hypoxia-Directed Cancer Therapeutics
Abstract
The hypoxia inducible factors (HIFs) bind to DNA and activate genetic programs required for driving solid tumor growth in cancers of kidney, pancreas, stomach, colon, and skin. These cancers are all listed as military relevance focus areas for Fiscal Year 2015 Peer Reviewed Cancer Research Program topics of research. The HIF proteins are required in these advanced tumors because their functions lead to increase blood flow, oxygenation, and nutrient availability to the growing and dividing tumor cells. Our proposed research seeks to identify a variety of drug-like molecules that are HIF inhibitors. By finding these inhibitors, we are seeking to block the progression of advanced human tumors. The inhibitors are needed for late-stage cancers when patients no longer respond to existing therapies. The HIF proteins have remained largely unexplored in the past as possible targets for cancer therapeutics, although there has been widespread recognition that they are essential for the progression of solid tumors. The past inability to exploit HIF drug-binding capabilities was due to the lack of three-dimensional structural understanding about their small molecule binding pockets. We have recently reported the first complete atomic structures for HIF proteins in a series of functionally revealing forms. This work clearly revealed five small molecule binding pockets inside the architecture of the functional HIF proteins where drug-like molecules can bind. We now seek to initiate the discovery of drug-like molecules that can bind to these HIF pockets directly. To make our discovery strategy successful, we will use purified HIF proteins and a chemical library of 32,000 small molecules that have established drug-like properties. Our drug screening strategy will look for molecules that bind tightly to the HIF proteins, and those hits will be then extensively analyzed to further identify those compounds that can inhibit HIF functions required for tumor progression. Our goal is to identify a variety of novel inhibitors for HIF proteins that are effective in cell culture studies, and this goal will be met within the 2-year funding period of this application. Beyond these studies, our longer-term objectives are to advance selected drug-like molecules identified in this proposal using synthetic chemistry, pharmacological assessment, and testing in a variety of animal tumor models. HIF targeted drugs can broadly impact both civilian and military personnel suffering from advanced cancers. The new treatment options that may ultimately emerge from this research would benefit patients with a variety of cancers that are currently resistant to existing treatments. HIFs are also the key drivers of advanced melanomas, a disease that has a particularly strong military relevance. Sixty-two percent of military personnel report sunburned skin when deployed abroad in desert and tropical zones, and malignant melanomas are disproportionately high within this population of military personnel.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610322
Entities
People
- Fraydoon Rastinejad
Organizations
- Sanford Burnham Prebys Medical Discovery Institute
- United States Army