Research Interest

Discovery and Development of Inhibitors of Cellular Stress Responses

Quality control of protein folding, trafficking and degradation is vital to the survival of cells. Tumour cells are especially dependent on molecular chaperones and related proteins that regulate protein homeostasis. These are attractive targets for new anticancer therapies.

Cancer drug targets in protein homeostasis.

Inositol Requiring 1 (IRE1) is an integral membrane protein in the endoplasmic reticulum which is critical in controlling the unfolded protein response. This cellular stress response ensures the correct folding, processing, export or degradation of proteins in the endoplasmic reticulum. IRE1 possesses both kinase and endoribonuclease enzyme activity. In response to unfolded proteins in the endoplasmic reticulum, IRE1 is activated and splices the mRNA for the transcription factor XBP1, leading to translation of spliced, active XBP1 protein. Dr Faith Davies and Prof Gareth Morgan in the Institute of Cancer Research have shown that spliced XBP1 is crucial for myeloma cell biology. We are investigating the development of inhibitors of IRE1 as potential agents for the treatment of multiple myeloma.

The HSP70 family of molecular chaperone ATPases are expressed in response to heat shock and other cellular stresses. In complexes with other proteins, the HSP70 proteins protect misfolded or unfolded client proteins from degradation, and refold them to restore client activity. HSP70 isoforms are overexpressed in many cancers. In collaboration with Professor Paul Workman and Dr Rob van Montfort we are using structure-based approaches to the discovery and optimisation of inhibitors of HSP70.