Group leader
Group members
Current research projects
We are interested in developing novel compounds that selectively target tumours,
either through selective activation within the tumour microenvironment, or by selectively
targeting proteins essential to the tumour cell's survival.
Bioreductive prodrugs
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Bioreductive drugs that are selectively activated to cytotoxins under hypoxia in
solid tumours have been a focus of the group. We have developed novel
benzotriazine dioxides as hypoxia selective cytotoxins as second generation
analogues of tirapazamine, in collaboration with Professor Bill Wilson, Dr
Frederik Pruijn and Dr Kevin Hicks of the Experimental Therapeutics Group. The
culmination of this work has been the discovery of SN30000 (now called CEN-209)
as a second generation benzotriazine dioxide. This class of compounds has been
licensed to Centella Therapeutics and is in clinical development with Cancer
Research UK. |
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A fundamental aspect of the search for improved bioreductive drugs is
understanding the radical chemistry of these agents. Studies to explore the
radical chemistry of the benzotriazine dioxides and related dioxides are being
conducted in collaboration with Associate Professor Bob Anderson and Dr Sujata
Shinde of the Free Radical Research group.
Collaborators:
Professor Bill Wilson,
Dr Frederik Pruijn,
Dr Kevin Hicks,
Experimental Therapeutics Group, Centella Therapeutics,
Cancer Research UK,
Assoc. Prof Bob Anderson,
Free Radical Research Group.
Related publications
Wilson, W.R., Hay, M.P. Targeting hypoxia in cancer therapy. Nature Rev. Cancer
11, 393–410, 2011 (PMID: 21606941).
Hicks, K.O., Siim, B.G., Jaiswal, J.K., Pruijn, F.B., Fraser, A.M., Patel, R.,
Hogg, A., Liyanage, H.D.S., Dorie, M.J., Brown, J.M., Denny, W.A., Hay, M.P.,
Wilson, W.R. Pharmacokinetic/pharmacodynamic modeling identifies SN30000 and
SN29751 as tirapazamine analogues with improved tissue penetration and hypoxic
cell killing in tumors. Clin. Cancer Res. 16, 4946–4957, 2010 (PMID:
20732963).
Hay, M.P., Hicks, K.O., Pchalek, K.1, Lee, H.H., Blaser, A., Pruijn, F.B.,
Anderson, R.F., Shinde, S.S., Wilson, W.R., Denny, W.A. Tricyclic 1,2,4-triazine
1,4-dioxides as hypoxia selective cytotoxins. J. Med. Chem., 51, 6853–6865, 2008
(PMID:18847185).
“New Zealand-designed anti-tumour agent to enter clinical development” PRESS RELEASE University of Auckland (link)
“Drug could halt fatal tumours” Herald on Sunday, June 5 2011 (link)
Anderson, R.F., Shinde, S.S., Maroz, A., Hay, M.P., Patterson, A.V., Denny, W.A.
Characterization of radicals formed following enzymatic reduction of
3-substituted analogues of the hypoxia-activated cytotoxin 3-amino-1,2,4
benzotriazine 1,4-dioxide (tirapazamine). J. Am. Chem. Soc. 132, 2591-2599, 2010
(PMID:
20141134).
Shinde, S. S., Hay, M. P., Patterson, A. V., Denny, W. A., Anderson, R. F.
Spin-trapping of radicals other than the *OH radical upon reduction of the
anticancer agent tirapazamine by cytochrome P450 reductase. J. Am. Chem. Soc.
2009, 131, 14220-14221 (PMID: 19772319).
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Developing novel radiosensitizers for SBRT
Nitroimidazole radiosensitizers have been the subject of investigation for several decades with only one agent being used clinically.
Technical advances in radiotherapy techniques have resulted in new therapies such as stereotactic beam radiotherapy (SBRT).
These new approaches have provided new opportunities for the use of radiosensitizers. We are developing 3rd generation radiosensitizers for use with SBRT.
We are exploring the development of novel nitroimidazole compounds whose radical and physicochemical properties have been optimised for use in conjunction with SBRT.
Collaborators:
Dr Kevin Hicks,
Dr Jingli Wang,
Dr Frederik Pruijn,
Experimental Therapeutics Group,
Centella Therapeutics,
Assoc. Prof Bob Anderson,
Free Radical Research Group.
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Synthetic lethal interactions with HIF & VHL
We are also developing small molecules that rely on synthetic lethality to
target tumour cells. This approach requires the presence or absence of a
particular protein, combined with a small molecule inhibitor, to produce tumour
cell death. In one example we have identified a novel class of compounds that
inhibit glucose uptake and are selectively cytotoxic to tumour cells when
Hypoxia-Inducible Factor-1 (HIF-1) is expressed. 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.
Collaborators:
Dr Jack Flanagan,
Molecular modelling,
Professor Amato Giaccia,
Ruga Corporation.
Related publications
Chan, D.A., Sutphin, P.D., Nguyen, P., Turcotte, S., Lai, E.W., Banh, A., Reynolds,
G.E., Chi, J.-T., Wu, J., Solow-Cordero, D.E., Bonnet, M., Flanagan, J.U., Bouley, D.M.,
Graves, E.E., Denny, W.A., Hay, M.P., Giaccia, A. J. Targeting GLUT1 and the Warburg Effect
in Renal Cell Carcinoma by Chemical Synthetic Lethality Science Trans. Med. 3, 2011 (PMID: 21813754).
Bonnet, M., Flanagan, J.U., Chan, D.A., Lai, E.W., Nguyen, P., Giaccia, A.J.,
Hay, M.P. 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, M. P., Turcotte, S., Flanagan, J. U., Bonnet, M., Chan, D. A., Sutphin, P.
D., Nguyen, P., Giaccia, A. J., Denny, W. A. 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, P.D., Chan, D.A., Hay, M.P., Denny, W.A., Giaccia, A.J. A
novel molecule targeting VHL-deficient Renal Cell Carcinoma that induces
autophagic cell death. Cancer Cell, 2008, 14, 90–102 (PMID:
18598947).
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Targeting tumour angiogenesis through Adrenomedullin-1
One of the hallmarks of cancer is increased formation of blood vessels (angiogenesis)
and this process is mediated, in part, by a hormone known as adrenomedullin (AM).
This project seeks to design and synthesize new agents that selectively inhibit the ability
of AM to promote angiogenesis by blocking the cellular target of this hormone. This target,
known as the AM receptor, is found on the surface of cells. AM acts through this receptor to
stimulate signalling and promote blood vessel growth. The receptor is made of two subunits;
between these is a groove, where AM binds to produce its effects.
We are using medicinal chemistry, combined with molecular modelling, to create new molecules
that block the access of AM to this groove and therefore reduce its activity in blood vessels.
These molecules will be tested for their ability to selectively bind to the AM receptor and to
stop AM signalling. This project represents the first steps towards identifying a new targeted
anticancer therapy.
Collaborators:
Dr Debbie Hay,
Dr Jack Flanagan,
Molecular Modelling.
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