Heat Shock Protein 90 (HSP90) Inhibitors

Signal Transduction and Molecular Pharmacology Team

Section: Cancer Research UK Cancer Therapeutics Unit

These agents bind to the ATP pocket in the N-terminal domain of the HSP90 molecular chaperone. Inhibition of the ATPase activity results in the depletion of HSP90 client proteins, particularly kinases that are involved in signal transduction and oncogenesis (including c-RAF-1, Akt/PKB and CDK4) together with mutant p53. Combinatorial inhibition of multiple oncogenic pathways provides the potential for broad spectrum single agent activity.

We have used gene expression microarray analysis and proteomics to identify a molecular signature of response to 17AAG, currently in clinical trial in the Royal Marsden Hospital. This includes interesting and potentially important changes in the expression of genes and proteins involved in protein acetylation and methylation.

We are now investigating a series of genes and proteins that may be involved in cellular response to HSP90 inhibitors, including Aha1, Cdc37, HSP70 and Bax. We are using the technique of RNAi to knock down the expression of candidate genes and hence determine the effect on sensitivity to HSP90 inhibitors.

In collaboration with Vernalis (Winnersh, UK) and Centre chemists, we have identified more potent and selective analogues of the pyrazole HSP90 inhibitor CCT0180159 which was discovered in-house by high throughput screening. These fully synthetic small molecule HSP90 inhibitors have nanomolar potency, a high degree of selectivity and show considerable promise for further development, as exemplified by the publication of VER-49009. The success of this project has led to a licensing agreement with Novartis to progress the development of the HSP90 inhibitors to the clinic.