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Chemical Probes for Epigenetics Drug Discovery

What is Epigenetics?

Epigenetics can be defined as heritable and acquired changes in gene function that occur without a change in the DNA sequence.

Superimposed on the genome of each cell is a layer of "epigenetic" information, consisting of chemical modifications to DNA and also to the histone proteins that package it in chromatin. Together, genome and epigenome form a complex regulatory network that modulates chromatin structure and genome function, controlling the timing, amount and identity of proteins expressed from each gene. In diseases, protein levels are often altered: for instance, in tumour cells specific proteins are often present at much higher levels than in normal cells. Researchers believe that by identifying how these parameters are controlled, they can better understand the factors that lead to many common diseases, such as cancer, diabetes, obesity and Alzheimer's disease, and use this information to discover new medicines.

Chemical modifications of histones include methylation of lysine and arginine residues, acetylation of lysine residues, and phosphorylation of serine and threonine residues. Many of the proteins effecting and detecting these modifications have only recently been identified.

About this project

This SGC-led initiative, funded by the Wellcome Trust, aims to develop "chemical probes", small molecules that can selectively stimulate or block the activity of a protein, specifically designed to affect the activity of proteins involved in epigenetic control. They will complement genetic knockouts and RNAi approaches to understand the role of these proteins in biology. The probes need to be highly selective for their target protein, and suitable for use in cellular settings. It is hoped that some probes may be a starting point for drug discovery.

The public-private partnership, led by the Structural Genomics Consortium (SGC), also includes GlaxoSmithKline (GSK), the National Institutes of Health Chemical Genomics Center (NCGC) in Bethesda, USA, and the Departments of Chemistry and Biochemistry at the University of Oxford.

In keeping with SGC policy, the structure and data associated with each probe will promptly be made freely available. Traditionally, pharmaceutical compounds have often only been released for public use after the relevant drug development program has been completed. It was thought that releasing an early-stage inhibitor would hamper further research in the corresponding area by the pharmaceutical sector, but history shows that the pharmaceutical industry is far more likely to pursue a drug discovery programme if there are already well-characterised inhibitors with defined mechanisms of action available.

A public-private partnership

This partnership is unique in that it brings the medicinal chemistry expertise within industry together with the biological expertise within academia to address an emerging area of biology. In this regard, the initiative may provide an excellent model for future interactions between academia and industry in the area of "pre-competitive chemistry".

Project partners