Medicinal Chemistry - Targeting hypoxia and HIF-1
Group Leader
Research Interests
Tumour Selectivity
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 cells survival.
Bioreductive Drugs
 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 the Experimental Oncology Group.
Aligned with this is the development
of bioreductive drugs that may be used in concert with enzyme-prodrug systems delivered
selectively to solid tumours. This work is
carried out in collaboration with Professor Martin Brown, Department of Radiation Oncology,
Stanford University.
We are also working with
Dr Jeff Smaill and Dr David Ackerly to optimise nitroreductase systems
for prodrug activation.
Small molecule inhibitors
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. Examples
include molecules that are selectively cytotoxic to tumour cells when Hypoxia-Inducible
Factor-1 (HIF-1) is operational, and another class of compounds that induce autophagy
in von Hippel-Landau Factor-deficient Renal Carcinoma Cells.
This work is in collaboration with Professor Amato Giaccia, Department of Radiation Oncology,
Stanford University.
Current Research Projects
- Development of hypoxia-selective cytotoxins based on the 1,2,4-benzotriazine dioxide
core.
- Development of novel prodrugs for Clostridia Delivered and Gene-Directed Enzyme
Prodrug Therapy (CDEPT and GDEPT).
- Design and synthesis of drugs that target hypoxia-inducible factor (HIF-1a).
- Development of novel drugs selectively targeting the loss of the Von Hippel Lindau
(VHL) tumour suppressor in tumour cells.
- Identification and development of novel heterocyclic N-oxides with activity against
Mycobacterium tuberculosis.
Group Members
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