Faculty of Medical and Health Sciences


Targeting molecular responses to hypoxia

Hypoxia-Inducible Factor-1 (HIF-1) dominates one arm of the molecular response to hypoxia.  In one approach we have screened small molecules for synthetic lethal combinations with HIF-1 to selectively produce tumour cell death. We have identified a novel class of compounds that inhibit glucose uptake and are selectively cytotoxic to tumour cells over expressing GLUT-1. Another novel class induces autophagy in von Hippel-Landau Factor-deficient renal carcinoma cells. Together with Dr Jack Flanagan we have used molecular modelling to understand the structure-activity relationships of this class. This work is being conducted in collaboration with Professor Amato Giaccia, Department of Radiation Oncology, Stanford University and has been licensed to Ruga Corporation.

The Unfolded Protein Response (UPR) is another arm of the integrated response to hypoxia. We are currently exploring small molecule inhibitors of the UPR in an effort to selectively kill tumour cells. This work is being conducted with Professor Albert Koong, Department of Radiation Oncology, Stanford University and Professor Costas Koumenis, Department of Radiation Oncology, University of Pennsylvania.

 

Funding

Financial support from US National Cancer Institute, NIH, Ruga Corporation Inc., Worldwide Cancer Research (Association for International Cancer Research), and The University of Auckland Faculty Research Development Fund is gratefully acknowledged.

 

Related Publications

Bonnet M, Flanagan JU, Chan DA, Giaccia AJ, Hay MP. Identifying novel targets in renal cell carcinoma: design and synthesis of affinity chromatography reagents. Bioorg. Med. Chem. 22, 712–720, 2014. (PMID: 24387866)

Chan DA, Sutphin PD, Nguyen P, Turcotte S, Lai EW, Banh A, Reynolds GE, Chi J-T, Wu J, Solow-Cordero DE, Bonnet M, Flanagan JU, Bouley DM, Graves EE, Denny WA, Hay MP, Giaccia AJ. Targeting GLUT1 and the Warburg Effect in renal cell carcinoma by chemical synthetic lethality. Science Trans. Med. 3, 2011 (PMID: 21813754).

Bonnet M, Flanagan JU, Chan DA, Lai EW, Nguyen P, Giaccia AJ, Hay MP. SAR studies of 4-pyridyl heterocyclic anilines that selectively induce autophagic cell death in von Hippel-Lindau-deficient renal cell carcinoma cells. Bioorg. Med. Chem. 19, 3347–3356, 2011 (PMID: 21561782).

Hay MP, Turcotte S, Flanagan JU, Bonnet M, Chan DA, Sutphin PD, Nguyen P, Giaccia AJ, Denny WA. 4-Pyridylanilinothiazoles that selectively target von Hippel-Lindau deficient renal cell carcinoma cells by inducing autophagic cell death. J. Med. Chem. 2010, 53, 787-797 (PMID: 19994864).

Turcotte S, Sutphin PD, Chan DA, Hay MP, Denny WA, Giaccia AJ. A novel molecule targeting VHL-deficient renal cell carcinoma that induces autophagic cell death. Cancer Cell, 2008, 14, 90–102 (PMID: 18598947).