School of Medical Sciences


Selective Inhibitors of Phosphoinositide 3-Kinases (PI3Ks)

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.

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