PKB (AKT) Kinase
Proliferation, angiogenesis and programmed cell death are three cellular activities often found deregulated in cancer. Protein kinase B (PKB)—also known as AKT—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 in human tumours. In addition the three closely related isoforms of PKB, α, β and γ(AKT, 1, 2 and 3) have been found mutated, 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.
In collaboration with Dr Ian Collins (Medicinal Chemistry Team 2) and other teams within Cancer Therapeutics, Professor David Barford (Structural Biology, ICR), who determined the crystal structure of PKBβ and Astex Therapeutics (Cambridge, UK) (Cambridge, UK) we have utilised crystallographic structure-based design techniques for the discovery of novel inhibitors of PKB. These inhibitors exhibit nanomolar potency toward PKB, inhibit the PI3 Kinase/PKB pathway in cells and show therapeutic activity in human tumour xenograft models. A clinical development candidate was announced in 2010 by AstraZeneca, based on research from this collaborative project.
Currently we are using compounds from this project as chemical probes to investigate potential mechanisms of resistance that may arise in the clinical setting. We are also using these small molecules to probe the pathways we are targeting and their relationship with one another in cancer. For example, we are currently using small molecule inhibitors discovered on the PKB/AKT and CHK1 projects as chemical probes to investigate how growth factor dependent cell signalling pathways may regulate cell cycle checkpoints.