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Today is the final day of reports from the 2010 meeting of the Society for Biomolecular Science in Phoenix. The meeting organizers have been excellent hosts and I’d like to express my sincerest thanks for their hospitality. After this, I have one last post containing all the interesting little observations and snippets of info that I deserve a mention, but didn’t fit into the larger topical posts. I also had some interesting discussions outside the official event that I’d love to continue online.

This morning’s session was on epigenetics and it probably won’t surprise my academic audience that pharma has, for the most part, passed on debating whether or not there is a histone code and has instead devoted itself to developing tools for writing, reading, and erasing epigenetic modifications. So what are they doing, then?

Histone Acetyltransferases (HATs) are the writers. They’ve developed high-throughput versions of an assay that detects acetylated lysine (the alphascreen assay) to a format which allows them to extend the usable range of the assay into the lower affinity region needed for screening and have found compounds from a compound library called LOPAC1280 which interfere in the assay.

To read the code, bromodomain containing proteins are used. There are 55 proteins that bind to acetylated lysines (sites of epigenetic modification), and because the proteins are actually quite different in their structure, they’re selective about which sites of epigenetic modification they preferentially attach themselves to. So the theory is that the selective binding will reveal the histone code. While it’s possible that up to 55 different patterns of modification can be discriminated by the various bromodomain binding patterns, it’s more likely that there will be significant overlap and the meaning, if any, of the different patterns isn’t yet known. Not to worry, though. Amy Quinn from the NIH Chemical Genomics Center and Tim Wigle from the UNC Integrative Center for Chemical Biology are screening compounds to see if they can disrupt the interaction of just one of these bromodomain proteins, which could then allow targeting of a specific gene with a epigenetic drug. Imagine for a moment, targeting the silenced tumor suppressors in a particular cancer subtype.

If the HATs are the writers of the code, the Histone Deacetylase Complex proteins (HDACs) are the erasers. From a drug discovery standpoint, this is an easier area to work in because you’re just looking for inhibitors of HDAC activity(of which there are already known cancer drugs). Dr. Wigle has done screening of a 100k compound library, finding 600 hits comprising 9 clusters of relevant activity and one cluster they’re not following up on. Looking at the LSD1 demethylase and its substrate the G9a peptide, his team found a class of compounds (UNC0224 and UNC0321) reaching down into the picomolar range in inhibitory strength (Ki). This is a great development, because existing HDAC inhibitors are quite toxic and if you have a compound with a low Ki, you can administer it at a lower dose and get the same level of inhibition with fewer or reduced side effects.

It appears it’s left up to academia to continue to decipher what the code means, but the tools for reading and writing have certainly improved.