School of Medical Sciences


Hypoxia-selective multikinase inhibitors (HSMKI)

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

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, PR610, has been selected by Proacta Inc. for clinical trials. PR610 shows remarkable activity against models of erlotinib-resistant lung cancer and is the World's first hypoxia activated prodrug against a tyrosine kinase receptor family. EGFR and HER2 are mutated or over-expressed in 60-90% of human carcinomas.

SN29966_chem

Related publications


Smaill, J.B., Abbattista, M., Jaiswal, J., Lu, G.L., Anderson, R.F., Ashoorzadeh, A., Denny, W.A., Doñate, F., Hsu, A., Lee, H.H., Maroz, A., Mehta, S., Pruijn, A, Puryer, M., Syddall, S.P., Thompson, A., van Leeuwen, W., Wilson, W.R., Jamieson, S. and Patterson, A.V. Mechanism of action of the hypoxia-activated irreversible pan-HER inhibitor SN29966. AACR-NCI-EORTC Int Conf Mol Targets Cancer Ther; Molecular cancer Therapeutics: 2011; 10 (11 Suppl): A247 (link)

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.

Trial for NZ-developed ‘Stealth’ cancer drug to start, TVNZ One news website, August 30th, 2012 (link)

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)