In the Cell Cycle Control Team, we are currently involved in a number of drug discovery projects on targets that regulate cell signalling, cell cycle checkpoints and DNA repair. These include the serine/threonine kinases PKB /AKT, CHK1 and CHK2, and a novel DNA repair target. A key role of the team in this activity is to understand, at the molecular level, the mechanism of action of compounds discovered on these projects—both in vitro (in cell lines) and in vivo. For example, for the PKB/AKT drug discovery project we have investigated the effects of project compounds on the phosphorylation status of known substrates of PKB/AKT, including GSK3beta, PRAS40 and FOXO1. Such potential markers of drug effect are often referred to as pharmacodynamic (PD) biomarkers and are becoming established as an important part of both preclinical drug discovery and clinical drug development.
A further aim of the team is to use the small molecules developed on these drug discovery projects as chemical probes for further target-based research. A key focus of this research is the identification of potential mechanisms of resistance that these small molecules may generate in the clinic. We are also using project compounds 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, which may lead to new target identification and thus new drug discovery.
We have also used our small molecules as tools to develop novel pharmacodynamic (PD) biomarker assays for late stage preclinical and early stage clinical evaluation of compounds. This research has led to the recent establishment of the Clinical PD Biomarker Group, within the Cell Cycle Control Team. The Group’s objectives are to develop and implement fit-for-purpose assays for the evaluation of PD biomarkers in Phase I clinical trials of new anticancer agents. The establishment of this group provides the opportunity for proof of mechanism studies of molecular targeted agents in the Phase I setting and to determine whether there is evidence that such assays may act as predictors of patient response. Whilst research to date has focussed on adult Phase I trials, a future avenue is the translation of these biomarkers into the paediatric setting.
- To discover and develop new drugs that act on molecular components of the cell division cycle, and its associated pathways, and to understand the mechanism of action of these drugs.
- To use the small molecules discovered on drug discovery projects as chemical probes to facilitate further research on our drug targets.
- To identify and develop PD biomarkers to be used in both preclinical drug development and Phase I clinical trials of our new molecular targeted anticancer agents.