Academic Staff

Teaching Responsibilities

• CHE2 Medicinal Chemistry
• CHE3 Medicinal Chemistry

Research Expertise

Research interests include the design, synthesis and evaluation of small molecule inhibitors of protein kinases and cyclic nucleotide phosphodiesterases. Particularly interested in PI3-kinase, JAK, PDK1, PDE2 and PDE3.

Also interested in the development and application of peptide nucleic acid (PNA) technology in the early detection and treatment of disease.

1. Novel Inhibitors of Phosphodiesterase 2

In collaboration with Dr. P. Thompson, Victorian College of Pharmacy

Cyclic nucleotide phosphodiesterases (PDEs) are important regulators of cellular function through the hydrolysis of the second messengers cAMP and cGMP. There are currently 11 different phosphodiesterase families, with over 50 isoforms described. As such, selective PDE inhibitors are becoming increasingly important to develop our understanding of the physiological roles of these enzymes and to identify potential therapeutic applications. Inhibitors of PDE3 and PDE5 are already being used as effective drugs, with other candidates in clinical trials.

2-Morpholinochromones, including the well-known PI3-kinase inhibitor LY294002, have been shown to inhibit human phosphodiesterases PDE2 and PDE3. Initial screening of synthetic 2-morpholinochromone analogues suggested increases in potency and selectivity can be made through relatively small structural modifications, as demonstrated by the PDE2 inhibitor BA54.

The aim of this project is to synthesise a library of novel 2-morpholinochromone analogues for evaluation as novel, potent and specific inhibitors of PDE2. There may also be the opportunity to be involved in the design of 2-morpholinochromones using a computational docking approach and to undertake biological testing of the synthesised compounds.

2. Design and Synthesis of PDK1 Inhibitors

In collaboration with Dr. D. Wilson and Prof. R. Brownlee

Growth factors exert many of their physiological effects through activation of phosphoinositide 3-kinase (PI 3-kinase) which phosphorylates PtdIns(4,5)P₂ to generate PtdIns(3,4,5)P₃, a key cell signalling second messenger. It is thought that PtdIns(3,4,5)P₃ plays a key role in regulating cell growth, development and survival by activating the PKB and S6K protein kinases. This is completed by phosphorylation by a common upstream 3-phosphoinositide dependent protein kinase (PDK1). The availability of a potent and specific PDK1 inhibitor would be invaluable for basic research in understanding the role of PDK1 in the mediation of cellular processes relevant to cancer and diabetes.

Recent work undertaken has looked at the synthesis of novel PDK1 inhibitors based upon a published Merck compound. This involved the synthesis of a number of analogues and also the proposed pharmacophore. A novel PDK1 inhibitor lead (BA19) was obtained which, together with the initial Merck compound, forms the basis of this project.

A. Design of PDK1 Inhibitors

(with Dr. D. Wilson and Prof. R. Brownlee)

This project would greatly benefit from the development of a molecular modeling system which could be used to evaluate potential inhibitors of PDK1. A number of protein crystal structures complexed with different ligands are known in the literature. These include PDK1-ATP (the natural ligand), PDK1-staurosporine (a potent but highly unselective PDK1 inhibitor) and PDK1-BIMs (these are poor PDK1 inhibitors). This should provide an excellent base from which to model both lead compounds and potential inhibitors.

B. Synthesis of PDK1 Inhibitors

The second aspect of the project is the synthesis of the potential PDK1 inhibitors as designed and identified using modeling techniques described above. Initial work will also be undertaken to evaluate possible alternative synthetic methods which could be used to generate analogues more efficiently.