Protein Kinase B Inhibitors

Cell Cycle Control Team

Section: Cancer Research UK Cancer Therapeutics Unit

Proliferation (regulated by the cell division cycle), angiogenesis and programmed cell death are three cellular activities often found deregulated in cancer. Protein kinase B (PKB) is a serine/threonine kinase, which regulates all three of these processes through substrate phosphorylation and is itself regulated through the PI3 kinase signalling pathway. The importance of the PI3 kinase/PKB pathway in tumorigenesis is recognised from the observation that the phosphatase PTEN, a negative regulator of PI3 kinase signalling, is a tumour suppressor protein and one of the most common targets of mutation/deletion in human tumours. In addition the three closely related isoforms of PKB, α, β and γ have been found amplified, overexpressed or inappropriately activated in a number of tumour types. These observations suggest that a wide range of cancers could respond therapeutically to inhibitors of PKB. The aim therefore is to identify potent and specific inhibitors of PKB to block tumour proliferation, angiogenesis and survival. This project was initiated in collaboration with Professor David Barford (Section of Structural Biology), who determined the crystal structure of PKBβ and provided protein for the development of a 384-well format high-throughput PKB screen by the Analytical Technology and Screening Team. This project was also augmented in 2003 by the signing of a collaborative agreement between The Institute, Cancer Research Technology (CRT) and Astex Technology Ltd (Cambridge, UK) who bring their expertise in fragment-based drug discovery to the development of novel inhibitors of PKBβ. Combining drug discovery technologies at both The Institute and Astex Technology Ltd has led to the discovery of a number of small molecule inhibitors of PKBβ. These inhibitors exhibit nanomolar potency toward PKB, inhibit the PI3 Kinase/PKB pathway in cells and show therapeutic activity in human tumour xenograft models.