The scientists used a highly specialized X-ray crystallography technique to solve the protein structure of hypoxia-inducible factors (HIFs), considered critical regulators of a tumor's response to low oxygen (hyopoxia). The research, published in the journal, Nature, and reported in Drug Discovery & Development, helps scientists in the quest for new drugs to treat tumors by cutting off their supply of oxygen and nutrients (http://www.dddmag.com/news/2015/08/scientists-solve-structure-important-protein-tumor-growth?et_cid=4720282&et_rid=45505806&type=cta).
As Fraydoon Rastinejad, Ph.D., professor in the Metabolic Disease Program at SBP, explained, "For the first time, we have solved the structures of both HIF1-alpha and HIF2-alpha complexed with the ARNT subunit, a configuration required for HIF functionality. Visualizing these multi-domain structures helps us understand their drug binding capabilities and takes us further toward the goal of developing drugs that inhibit the tumor promoting effects of HIFs."
HIF proteins regulate genes that are important to the progression of a broad range of tumors, and altering their activity could be a promising approach for cancer therapy. While there have been major efforts to find drugs to inhibit HIF pathways, the only drug candidates to emerge from these efforts have been those that bind to another class of proteins called PHDs. PHD proteins regulate HIF activities, and there are many PHD inhibitors currently in clinical trials for anemia, chronic kidney disease, stroke and cancer.
According to an article in the Journal of Cell Biochemistry [2013 May;114(5):967-74. doi: 10.1002/jcb.24438, HIFs, angiogenesis, and cancer. Yang Y, Sun M, Wang L, Jiao B], "Tumor hypoxia was first described in the 1950s by radiation oncologists as a frequent cause of failure to radiotherapy in solid tumors. Today, it is evident that tumor hypoxia is a common feature of many cancers and the master regulator of hypoxia, hypoxia-inducible factor-1 (HIF-1), regulates multiple aspects of tumorigenesis, including angiogenesis, proliferation, metabolism, metastasis, differentiation, and response to radiation therapy. Although the tumor hypoxia response mechanism leads to a multitude of downstream effects, it is angiogenesis that is most crucial and also most susceptible to molecular manipulation. The delineation of molecular mechanisms of angiogenesis has revealed a critical role for HIF-1 in the regulation of angiogenic growth factors" (http://www.ncbi.nlm.nih.gov/pubmed/23225225).
Rastinejad explained that the new study "advances efforts to find new drugs that bind to HIF directly, rather than PHDs. We identified five different pockets in the architecture of the HIF complexes, all of which may be used for targeting small-molecule inhibitors. These drugs could conceivably inhibit HIF functions by reducing their stability, their ability to interact with other protein partners, and by altering mechanisms critical for their function."
Drugs that inhibit HIFs may be able to treat solid tumors. These cancers outgrow their blood supply and grow starved for oxygen, triggering HIFs to turn on genes that regulate many cancer cell survival pathways. The pathways include angiogenesis, erythropoiesis, increased expression of genes associated with anaerobic metabolism and metastasis.
Rastinejad concluded, "Our next step is to analyze a large number of patient samples with mutations in HIF proteins. We'd like to see where on the protein architectures these mutations occur, and how they manifest into HIF functional aberrations,". "Such mutations will offer a powerful glimpse into the structure-function activities of HIFs, and help us figure out how they turn genes on and off. The insights we make into the structure, function, and regulation of HIFs may also progress the development of treatments for a range of disease states beyond cancer, including heart disease, fatty liver, diabetes, and inflammatory diseases."