Research Interest
Discovery and Development of Kinase Inhibitors as Anticancer Drug
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 Cancer Therapeutics Unit, Professor David Barford of the Institute of Cancer Research, and Astex Therapeutics (Cambridge) we have applied structure-based design techniques to advance the in vitro and in vivo optimisation of lead compounds as inhibitors of PKB. Hits from a fragment-based screen were progressed to potent and selective pyrrolopyrimidine PKB inhibitors with oral efficacy in preclinical models. Intellectual property from this project is licensed to AstraZeneca and a pyrrolopyrimidine PKB inhibitor AZD5363 is in clinical trials, including studies at the Royal Marsden Hospital.
Evolution of potent and selective PKB inhibitors by fragment growing.
Cell Cycle Kinase Projects
Several 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 through sensing DNA-damage and initiating repair, while halting the cell cycle. Many tumours are deficient in early phase DNA-damage checkpoints, due to mutation or deletion in the p53 pathway, and thus become dependent on the later S and G2/M checkpoints for DNA repair. This provides an opportunity to selectively target tumour cells to enhance the efficacy of ionising radiation or widely used DNA-damaging cancer chemotherapies. Inhibitors of the checkpoint kinase CHK1 are of particular interest for combination with genotoxic agents. In collaboration with Dr Michelle Garrett and Sareum (Cambridge) we have used structure-based design to optimise the biological activity of hits identified through fragment-based screening against the cell cycle kinase CHK1.
Evolution of potent and selective CHK1 inhibitors by scaffold morphing.
The checkpoint kinase CHK2 has a distinct but less well characterised biological role to that of CHK1. Selective inhibitors would be valuable as pharmacological tools to explore the biological consequences of CHK2 inhibition in cancer cells. In collaboration with Dr Michelle Garrett’s team, and Professor Laurence Pearl, we have used structure-based and ligand-based approaches to develop selective inhibitors of CHK2.
Structure-guided design of a novel CHK2 inhibitor.
