Epigenetics
EPIGENETICS
an emerging target class for drug screening
By Dr John Comley
Figure 1: This image depicts the wrapping of DNA around histone octamers (greenish/blue spheres) to form nucleosomes, the organisation of nucleosomes into higher order chromatin structure and the compaction of chromatin into chromosomes (a metaphase chromosome in this case). The blue and yellow balls represent DNA methylation, ie methyl groups added to cytosine residues which serves as an epigenetic mark regulating many genome- dependant processes
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Heightened awareness of the potential importance of epigenetic targets in many disease areas, and growing vendor interest in developing new assays to screen DNA methylation and histone modifications encouraged HTStec to undertake market research in this area in June 2010. The study concluded epigenetic screening was still very much in its infancy and there was a need for new and improved screening tools and assays. Assay specificity, producing active protein and the availability of good antibodies were all cited as key obstacles. Much attention is coming from oncology areas and interest is particularly high in the assaying histone deacetylases (HDAC & Sirtuins), histone methyltransferases (HKMT & HRMT), histone demethylases (HDM), DNA methyltransferases (DNMT) and histone acetyl transferases (HAT). Epigenetic target assays are increasingly being attempted utilising a wide range of different screening technologies. Some of the more generic approaches currently being developed and validated are suitable for all types of histone substrates, and have application across a diverse range of histone modifications. The breadth of assays becoming available will soon extend well beyond the HDAC & Sirtuins. These approaches now need to be translated into a set of robust ready- to-use assay kits or tool-box reagents to open up the epigenetic field to HTS. An increasing number of vendors also now offer fee-for-service screening and profiling against epigenetic targets, such that outsourced compound testing against a panel of epigenetic assays is becoming a real possibility. In conclusion, the tools required to support epigenetic screening are fast emerging as our knowledge and experience with these targets increases, such that we can expect to see greater adoption or external use of these assays by Pharma and Biotech lead discovery programmes over the coming years.
Drug Discovery World Spring 2011
Image supplied by Active Motif
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