Group leader
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Quote
"The way to get good ideas is to get lots of
ideas, and throw the bad ones away." Dr Linus Pauling
(American theoretical chemist 1901-1994).
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Read more about
Dr Jeff Smaill
Senior Scientists
Overview
Inhibition of protein kinases is the central focus of modern oncology drug
development. Therapeutics targeted at Bcr-Abl, mutant EGFR (ErbB1, HER1) and
ErbB2 (HER2) are approved for use. In addition, small molecule inhibitors of
mutant B-Raf are demonstrating impressive efficacy and are likely to gain
approval.
We have had a long-running interest in the selective targeting of protein
kinases such as the ErbB family, PDGFR, Wee1 and CHK1 most notably including the
development of canertinib dihydrochloride (CI-1033) in collaboration with Pfizer
GRD. Canertinib was the first irreversible pan-ErbB inhibitor to enter human
clinical trials. The active pharmacophore of canertinib has acted as the
template for a further four irreversible pan-ErbB inhibitors that have entered
clinical trial.
In recent years there has been an increased focus on the development of
multikinase or “spectrum-selective” kinase inhibitors. This ”many targets”
design is intended to address resistance and efficacy limitations of kinase
selective inhibitors, brought about by inherent redundancies in cancer cell
signal transduction networks. Arguably the multikinase inhibitor derivatives
have resulted in an increased toxicity profile and have not fulfilled early
expectations. A central aspect of our work is to develop bioreductive prodrugs
of multikinase inhibitors (MKIs), termed hypoxia-selective multikinase
inhibitors (HSMKIs), thereby exploiting tumour hypoxia as a therapeutic target
that allows selective delivery of multikinase inhibitors to the tumour. We are
also interested in other classes of bioreductive prodrugs for hypoxia, as well
as activation by exogenous nitroreductase enzymes introduced to tumours by
conditionally replicating (gene therapy) vector technologies.
Current Research Projects
Students
Current students:
Alexandra Mowday* (PhD candidate)
Ritu Mittra* (MHSc candidate)
Shevan Silva* (MSc candidate)
Past students:
Jiechuang Su* (BSc Hons, 2008)
* co-supervision
