PI3 Kinase Inhibitors

Signal Transduction and Molecular Pharmacology Team

Section: Section of Cancer Therapeutics (including the Cancer Research UK Centre for Cancer Therapeutics)

Phosphatidylinositol 3 kinases (PI3 kinases) are important in controlling various aspects of the malignant phenotype, including proliferation, survival/apoptosis, adhesion/mobility, angiogenesis and also cell size. The PI3 kinase pathway is validated genetically by loss of the PTEN gene and also by amplification and mutation of PI3K3CA gene that encodes the p110α PI3 kinase isoform.

We are evaluating the mode of action and therapeutic potential of potent and selective PI3 kinase inhibitors that we have discovered with our academic collaborators and Yamanouchi Pharmaceutical Company and that are now being developed in association with PIramed (Slough, UK). Using gene expression microarray analysis we have identified a wide range of genes that show altered expression in response to PI3 kinase inhibition produced by pharmacological inhibitors or by genetic means.

This is helping us to understand the cellular mechanism of action of PI3 kinase inhibitors and to discover pharmacodynamic markers for use in the evaluation of the novel inhibitors that we are developing. The inhibitors exhibit nanomolar potency and a high degree of selectivity for p110α and p110β PI3 kinase. Activity is retained against two of the common mutant forms of p110α. A high degree of sensitivity is seen in cancer cells in which the PI3 kinase pathway is activated. Therapeutic activity has been demonstrated in human tumour xenograft models, including gliomas. The molecular mechanism of action of the PI3 kinase inhibitors is being explored in glioma models. Promising activity is also being seen with PI3 kinase inhibitors in combination with taxanes in prostate cancer models. A candidate has been selected to enter Phase I trials around the end of 2005.