Epigenetic Targets for Cancer Drug Discovery: Bromodomains and Beyond

Mark Bunnage1

1Pfizer, Cambridge, MA, USA


Epigenetics can be defined as heritable or acquired changes in gene expression that occur without a change in the underlying DNA sequence.   In addition to its genome, each human cell also contains epigenetic information that is encoded through chemical modifications to the DNA itself and also the histone proteins around which DNA winds to package it in chromatin.  This epigenetic signature plays a key role in modulating chromatin structure and genome function, thus helping regulate the protein expression profile in the cell. Since a hallmark of cancer is aberrant gene expression, research into epigenetics has great promise to enable future cancer drug discovery.

Chemical modifications of histones that influence epigenetic regulation include changes such as methylation of lysine/arginine residues and acetylation of lysine residues.  A number of enzymes have now been identified that either introduce these epigenetic marks (‘writers') or remove them (‘erasers'). In addition, regulatory proteins have been discovered that directly recognise histone modification status (‘readers') and drive the localisation of complexes that control gene expression.

This presentation will provide a perspective on small molecule drug discovery for epigenetic targets in cancer, with a particular focus on the bromodomain class of 'reader' proteins.