School of Medical Sciences


Medicinal Chemistry - Next generation bioreductive prodrugs

Group leader


Read more about Dr Jeff Smaill

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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).

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.

Students


Current students:

Alexandra Mowday* (PhD candidate) 

Past students:

Ritu Mittra* (MHSc, 2011) 
Shevan Silva* (MSc, 2011) 
Jiechuang Su* (BSc Hons, 2008)  

* co-supervision