Epigenetics - Chemical Probes for 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, the Ontario Research Fund and the Swedish Foundation for Strategic Research, 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 cellular role of these proteins. The probes need to be 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), Novartis, Pfizer, Eli Lilly, the National Institutes of Health Chemical Genomics Center (NCGC) (Bethesda USA), the Ontario Institute for Cancer Research and the Nuffield Dept. of Clinical Medicine, the Nuffield Dept. of Orthopaedics, Rheumatology and Muscoloskeletal Sciences, the Center for Integrative Chemical Biology and Drug Discovery at the University of North Carolina at Chapel Hill, the Departments of Chemistry and Biochemistry at the University of Oxford and the Department of Chemistry at Umeå University (Sweden).

In keeping with SGC policy, the structure and data associated with each probe will promptly be made available. Traditionally, pharmaceutical compounds have often only been released for public use after the relevant drug development program has been completed. It is commonly believed that releasing an early-stage inhibitor into the public domain 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".