Project Leaders
Translational Therapeutics Main Page
Over the last 50 years it has become widely accepted that human solid tumours
are often deficient in oxygen (known as hypoxia). This tumour hypoxia causes
resistance to cancer treatments such as chemotherapy and radiotherapy and makes
cancers more aggressive and likely to spread. Scientists have been working to
develop hypoxia-activated prodrugs that target and kill these low oxygen cells
which are common in tumours but rare in normal tissues. To date, all examples of
hypoxia-activated prodrugs have employed genotoxic DNA damaging agents that are
'masked' by oxygen-labile chemical groups (triggers).
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Human tumours stained for hypoxic cells |
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We are exploring the use of receptor
tyrosine kinase inhibitors as an alternate starting point for hypoxia-activated
prodrug design. By targeting protein kinases, it is theoretically possible to
avoid key dose-limiting toxicities, such as bone marrow toxicity, as well as arrive at
innovative chemical matter. We have developed a prototypical prodrug called
SN29966 which can release an irreversible inhibitor for the HER family (EGFR,
HER2, HER4) selectively in hypoxic tumour cells (HER3 does not have an active
kinase domain). This prodrug has excellent single agent activity against HER
driven tumour models, in part due to its remarkable pharmacokinetic properties.
The redox properties of this prodrug class is under evaluation in collaboration
with A/Prof Bob Anderson. A lead compound from the series, PR509, has been
selected by Proacta Inc. for IND-enabling studies.
Collaborators:
Associate Professor Bob Anderson
Keywords:
Tumour hypoxia,
Chemotherapy,
Radiotherapy,
Hypoxia-activated prodrugs,
Tyrosine kinase
inhibitors,
Targeting protein kinases,
SN29966,
EGFR/ErbB1, HER2/ErbB2, HER3/Erb3 (ERBB3),
HER4/Erb4 (ERBB4),
PR509,
Proacta Inc.
Related publications
Smaill, J.B., Lu, G.L., van Leeuwen, W., Abbattista, M.R., Anderson, R.F.,
Denny, W.A., Donate, F., Jasiwal, J., Maroz, A., Puryer, M., Syddall, S.P.,
Wilson, W.R., Patterson, A.V. Design and identification of the novel
hypoxia-activated irreversible pan-HER inihibitor SN29966. AACR-NCI-EORTC Int
Conf Mol Targets Cancer Ther; Molecular Cancer Therapeutics: 2009; 8 (12 Suppl):
C46 (link)
Patterson, A.V., Jaiswal, J., Syddall, S.P., Abbattista, M.R., van Leeuwen, W.,
Puryer, M., Thompson, A., Hsu, A., Mehta, S., Lu, G.L., Denny, W.A., Wilson,
W.R., Smaill, J.B. Cellular metabolism, murine pharmacokinetics and preclinical
antitumour activity of SN29966, a novel hypoxia-activated irreversible pan-HER
inhibitor. AACR-NCI-EORTC Int Conf Mol Targets Cancer Ther; Molecular Cancer
Therapeutics: 2009;8 (12 Suppl): B76 (link)
Lu, G. L., Smaill, J. B., Abbattista, M. R., Anderson, R. F., Ashoorzadeh, A.,
Denny, W. A., Donate, F., Hsu, A., Jaswail, J., Jamieson, S., Lee, H. H., Maroz,
A., Mehta, S., Pruijn, A., Syddall, S. P., Thompson, A., van Leeuwen, W.,
Wilson, W. R., and Patterson, A. V. Characterization of novel hypoxia-activated
prodrugs of irreversible pan-HER inhibitors. Proceedings of the 101th Annual
Meeting of the American Association for Cancer Research; Apr 2010; Washington,
D.C., Abstr LB-297 2010.
TVNZ7 releases documentary on discovery and development of HSMKI prodrug
(Video), August 24th, 2011 (link)
"Foreign teams to work on promising NZ drug", The New Zealand Herald, February
25th, 2011.(link)
"Kiwis design cancer stealth fighter", The National Business Review, March 18th,
2011.
(link)
Cancer Society Auckland News letter, Issue 2, 2010.
(link)
SEEK magazine, Maurice Wilkins Centre
for Molecular Biodiscovery, Issue 3, 2009. (link)
"NZ Scientists find new cancer drug", The Dominion Post, November 28th 2009. (link)
"NZ-designed drug shows exciting early promise against lung cancer", Press
Release, Maurice Wilkins Centre for Molecular Biodiscovery, November 25th 2009.
(link)
