Sunday, April 18, 2010

SBS 2010 Conference: Epigenetics – an Emerging Target Class for Drug Discovery

Epigenetics refers to the changes in gene expression (phenotype) caused by mechanisms other than direct transcription of DNA sequence. Commonly this involves methylation of DNA or post-translational modifications to the machinery involved in transcription. A classic example of epigenetics as discuused by Manfred Jung, the plenary lecturer of the opening session, is in the birds and the bees – well, specifically the bees. Young bees that ingest pollen become worker bees, induced to collect nectar for the benefit of the colony; those that ingest royal jelly can become the queen, responsible for the procreation and annual continuation of the colony.

Epigenetic machinery includes DNA methylation, micro-RNA and histone modifications. It was largely this latter biochemical activity that concerned this track as a possible target for drug discovery as numerous diseases are thought to be associated with aberrant histone post-translational modifications.

The histone code is thought to be comprised of a series of writers, eraser and readers as described by Ann Quinn of the NIH Chemical Genomic Center. The writers are responsible for post-translationally modifying histones with functional groups such as methyl, acetyl, ubiquityl, phosphoryl, and a number of other groups. The erasers serve to remove these groups in a reversible manner. Finally the readers are a group of proteins with specific tertiary structure suitable for binding histone post-translational modifications and induce changes in phenotype.

Alan Kozikowski opened the second session discussing inhibitors of histone deacetylase (HDAC), an eraser. This group of enzymes serves to remove acetyl groups from histones and is a popular drug target. Its counterpart writer, histone acetylase (HAT), acetylates histones causing the DNA-chromatin complex to assume a relaxed configuration which leads to increase gene transcription. HDAC removes the acetyl group causing the complex to constrict into a tight configuration which essentially shuts off transcription (see Figure 1).

Figure: The Activity of HATs and HDACs Regulate Chromatin Structure and Transcription. HATs acetylate lysine residues (K) of the histones and HDAC removes the acetyl group.

HDAC inhibitors are used in oncology applications associated with silencing of tumor suppressor genes. By inhibiting the deacetylation of the histone, it is thought that the tumor suppressors can be expressed.

Other members of the histone code were also discussed as drug targets, such as the royal family of methyl-lysine binding proteins – readers. Tim Wigle of the Center for Integrative Chemical Biology and Drug Discovery gave a talk concerning these interactions and noted that assay development was difficult as the protein:protein interaction is typically weak requiring uneconomical amounts of protein. He noted that the avidity of AlphaScreen can be used to lower protein requirements and create a practical assay.

It appears that epigenetic drug discovery is a burgeoning field and generated much interest at SBS. Look to further developments in 2011.

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