Principal investigators
Associate investigators
Research interests
Human cancers each have key individual characteristics, in many cases involving
a change to a single enzyme, which are vital for their survival. Targeted anticancer
therapy involves identifying such target enzymes, generally present in only a proportion
of cancers, and designing specific drugs to inhibit them. A good example for such
an approach involves enzymes called phosphoinositide-3-kinases, which play many
important roles in the behaviour of the normal tissues of our body.
Recent results show that one member of this family, called p110-alpha, is mutated
in certain cancers and sustains their survival and resistance to therapy.
Our challenge
is to develop new highly specific inhibitors of this enzyme that do not affect other
family members and thus have minimal side effects.
To this end, we have assembled a research team comprising medicinal chemists, cell
and molecular biologists, a pharmacologist and a computer molecular modeller, in
an integrated approach to develop new candidate drugs for clinical trial.
Contact person
Publications
- Kim JE, Shepherd PR, Chaussade C. Investigating the role of class-IA
PI 3 –kinase isoforms in adipocyte differentiation. Biochem Biophys Res Commun 2009,
379, 830-834.
- Chaussade C, Rewcastle GW, Kendall JD,
Denny WA, Cho K, Gronning LM, Chong ML, Anagnostou SH, Jackson SP, Daniele
N, Shepherd PR. Evidence for functional redundancy of class-IA PI 3-kinase isoforms
in insulin signalling. Biochem J 2007, 404, 449-458.
- Frederick R, Denny WA. Phosphoinositide-3-kinases (PI3Ks): Combined
comparative modeling and 3D-QSAR to rationalize the inhibition of p110α. J Chem
Inf Model 2008, 48, 629-638.
- Kendall JD, Rewcastle GW, Frederick R, Mawson
C, Denny WA, Marshall ES, Baguley BC, Chaussade
C, Jackson SP, Shepherd PR. Synthesis, biological evaluation and
molecular modelling of sulfonohydrazides as selective PI3K p110α inhibitors. Bioorg
Med Chem 2007, 15, 7677-7687.
- Jackson SP, Schoenwaelder SM, Goncalves I, Nesbitt WS, Yap CL, Wright CE, Kenche
V, Anderson KE, Dopheide SM, Yuan Y, Sturgeon SA, Prabaharan H, Thompson PE, Smith
GD, Shepherd PR, Daniele N, Kulkarni S, Abbott B, Saylik D, Jones
C, Lu L, Giuliano S, Hughan S,C, Angus JA, Robertson AD, Salem H. PI 3-kinase p110a: a new target for antithrombotic therapy.
Nature Med 2005 11, 507-514.
- Shepherd PR. Mechanisms regulating phosphoinositide 3-kinase signalling
in insulin-sensitive tissues. Acta Physiol Scand 2005, 183, 3-12.
- Schoenwaelder S.M, Ono A, Sturgeon S, Chan SM, Mangin P, Maxwell MJ, Turnbull S,
Mulchandani M, Anderson K, Kauffenstein G, Rewcastle, GW, Kendall
J, Gachet C, Salem HH, Jackson SP. Identification of a Unique Co-operative Phosphoinositide
3-Kinase Signaling Mechanism Regulating Integrin aIIbb3 Adhesive Function in Platelets. J. Biol.
Chem 2007, 282, 28648-28658.
Funding
Major funding is provided by the Health Research Council, the Maurice Wilkins Centre
for Molecular Biodiscovery and Pathway Therapeutics Ltd. Additional support is provided
by the Auckland Cancer Society and The University of Auckland Faculty Research Development
Fund.
