Discovery and Development of Kinase Inhibitors as Anticancer Drugs
Section: Cancer Research UK Cancer Therapeutics Unit
Signal Transduction Kinase Projects
Protein kinase B (PKB/Akt) is a signal transduction kinase that is part of an important network for transmitting external growth signals to the cell nucleus. Upregulation of the activity of this kinase is a feature of several tumour types. In collaboration with Dr Michelle Garrett and other teams within the Centre, Professor David Barford of The Institute of Cancer Research, and Astex Therapeutics, Cambridge, we have applied crystallographic structure-based design techniques to advance the in vitro and in vivo optimisation of lead compounds as inhibitors of PKB.
Inositol Requiring 1 (IRE1) is a an endoplasmic reticulum transmembrane protein involved in controlling the Unfolded Protein Response, which ensures the correct folding, processing, export or degradation of proteins emerging from the endoplasmic reticulum. IRE1 possesses both kinase and endoribonuclease enzyme activity. In collaboration with Dr Faith Davies and Prof Gareth Morgan in The Institute of Cancer Research, we are investigating the development of inhibitors of IRE1 as potential agents for the treatment of multiple myeloma.
Cell Cycle Kinase Projects
A number of kinase enzymes are important in the control of the cell growth and replication cycle. These enzymes may drive progression through the cell cycle, or alternatively can act as regulators at specific checkpoints that ensure the integrity of DNA replication. In collaboration with Dr Michelle Garrett and Dr Wynne Aherne’s teams, and Sareum Limited, Cambridge, we are using crystallographic structure-based design to optimise the biological activity of hits identified through fragment-based screening against the cell cycle kinase CHK1.
In collaboration with Dr Michelle Garrett’s team, and Professor Laurence Pearl, we have used structure-based and ligand-based approaches to develop inhibitors of the cell cycle regulatory enzyme CHK2.
In the Cancer Research UK Cancer Therapeutics Unit
