Chromatin Modification

Section: Cancer Research UK Cancer Therapeutics Unit

Modulation of Histone Methylation as an Approach to Cancer Therapy

Recently, methylation on specific histone lysine residues has been recognised to have an important role in the regulation of transcription. Although target validation in this emerging area is not yet complete, inhibitors of histone methylation may provide a novel therapeutic approach to the treatment of cancer. A high-throughput screen has been completed to identify inhibitors of the histone methyltransferase, SET7/9. Selected hits will be evaluated using a range of secondary biochemical and cell-based assays that have been established in the laboratory. These assays will also be used to evaluate compounds identified in an in silico screen for SET7/9 inhibitors. Work is in progress using molecular tools e.g. siRNA knockdown to provide additional information to validate this class of enzymes as cancer drug targets.

Modulation of Histone Acetylation as an Approach to Cancer Therapy

Histone acetylation has a key role to play in the regulation of gene expression and is mediated by histone acetyltransferases (HATs) and histone deacetylases (HDACs). Both enzyme classes are attractive anticancer targets. We originally identified a range of isothiazolone compounds as inhibitors of histone acetyltransferase activity. These compounds are thiol reactive and medicinal chemistry was initiated to improve the pharmaocological properties of this series of compounds. More recently our work has focussed on the development of inhibitors of HDACs. In collaboration with Chroma Therapeutics potent hydroxamic acid HDAC inhibitors have been identified and their pharmacological properties evaluated. Chemical optimisation of this series of compounds towards selection of a clinical candidate is underway. A range of secondary assays has been developed to evaluate the cellular effects of HDAC inhibitors and for determining their pharmacodynamic properties.

Samples from patients in a Phase I trial (Protocol No.2032) of the hydroxamic acid HDAC inhibitor LAQ824 have been analysed. Hyperacetylation of histones, a biomarker of HDAC inhibition, was shown to occur in a dose- and time-related manner. In view of the importance of HSP90 as a cancer drug target, we have evidence, supported by in vitro data, to suggest that inhibition of the molecular chaperone may contribute to the antitumour effects of HDAC inhibition. The effects of HDAC inhibitors on gene expression are being studied using microarray technology and, using immunohistochemistry and human tumour tissue arrays, the expression of selected HATs and HDACs, as well as the extent of cellular acetylation in relation to tumour type and grade is currently being determined.