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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: Twitter: Dereklowe

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January 18, 2012

Fun With Epigenetics

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Posted by Derek

If you've been looking around the literature over the last couple of years, you'll have seen an awful lot of excitement about epigenetic mechanisms. (Here's a whole book on that very subject, for the hard core). Just do a Google search with "epigenetic" and "drug discovery" in it, any combination you like, and then stand back. Articles, reviews, conferences, vendors, journals, startups - it's all there.

Epigenetics refers to the various paths - and there are a bunch of them - to modify gene expression downstream of just the plain ol' DNA sequence. A lot of these are, as you'd imagine, involved in the way that the DNA itself is wound (and unwound) for expression. So you see enzymes that add and remove various switches to the outside of various histone proteins. You have histone acyltransferases (HATs) and histone deacetylases (HDACs), methyltransferases and demethylases, and so on. Then there are bromodomains (the binding sites for those acetylated histones) and several other mechanisms, all of which add up to plenty o' drug targets.

Or do they? There are HDAC compounds out there in oncology, to be sure, and oncology is where a lot of these other mechanisms are being looked at most intensively. You've got a good chance of finding aberrant protein expression levels in cancer cells, you have a lot of unmet medical need, a lot of potential different patient populations, and a greater tolerance for side effects. All of that argues for cancer as a proving ground, although it's certainly not the last word. But in any therapeutic area, people are going to have to wrestle with a lot of other issues.

Just looking over the literature can make you both enthusiastic and wary. There's an awful lot of regulatory machinery in this area, and it's for sure that it isn't there for jollies. (You'd imagine that selection pressure would operate pretty ruthlessly at the level of gene expression). And there are, of course, an awful lot of different genes whose expression has to be regulated, at different levels, in different cell types, at different phases of their development, and in response to different environmental signals. We don't understand a whole heck of a lot of the details.

So I think that there will be epigenetic drugs coming out of this burst of effort, but I don't think that they're going to exactly be the most rationally designed things we've ever seen. That's fine - we'll take drug candidates where we can get them. But as for when we're actually going to understand all these gene regulation pathways, well. . .

Comments (15) + TrackBacks (0) | Category: Biological News | Cancer | Drug Development


1. luysii on January 18, 2012 11:40 AM writes...

For a quick glance at the complexity of it all see Cell vol. 147 pp. 1628 - 1539 '11 (last paper of the old year) where they describe how the epigenetic modifications (histone code primarily) and the enzymes which add and subtract them (e.g. write and erase them) and the proteins that bind to them (read them) occur in combinatorial patterns. Drug discovery here won't be simple, but at least one can see the complexity of the target we're trying to modify.

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2. JIA on January 18, 2012 11:43 AM writes...

Hi Derek,
This blog post wasn't prompted by the Genentech-Constellation deal yesterday, was it?

Word is that Genentech is changing direction away from receptor tyrosine kinases and towards epigenetics and tumor metabolism - in fact they laid off some biologists in research last week as part of the changing project focus, so they seem quite serious about it.

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3. Curious Wavefunction on January 18, 2012 11:46 AM writes...

Drug discovery for epigenetic targets might be a good example of the principle that in science, prediction or practical success doesn't always equal real understanding.

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4. patentgeek on January 18, 2012 11:48 AM writes...

Difficulties to be overcome there will be, but epigenetics is well worth pursuing for therapeutic approaches. It has taken many years to get to the current burst of interest. Decitabine (Dacogen), an inhibitor of DNA methyltransferase currently marketed for myelodysplastic syndrome, has been around since the '60s. Folks like Richard Momparler and Joe DeDimone were lone voices in the wilderness for decades with their proposals that low doses of the drug could lead to hypomethylation of CpG islands and reactivation of tumor suppressor genes. As recently as the late '90s, this was pooh-poohed by many. The approvals of azacytidine in 2004, and decitabine in 2006, were vindications for these folks.

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5. Student on January 18, 2012 11:58 AM writes...

Looking upstream of anything (in this case protein) is good if that upstream factor is the cause of the phenotype. But as is common sense, if something is upstream, the reason so is because it is affecting multiple things...otherwise there would be no need for it. And with that comes the obvious hurtle of upstream manipulation having huge differences in multiple downstream pathways. I know I'm just being pedantic here, but this is something they shouldn't forget.

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6. exCHEM on January 18, 2012 12:07 PM writes...

Vorinostat and other HDAC inhibitors haven't done that well outside of the niche indications, looks like vorinostat won't make it in myeloma either. Maybe the 2nd generation, more potent compounds might give better results in the clinic.

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7. biotechbaumer on January 18, 2012 12:11 PM writes...

I'm totally keen on this area of DD and think it could very well lead to the same fruitful results we've seen with kinases over the past 20 years. I'd also argue that there is alot of room for 'rational' uses of these drugs in certain indications. As you mentioned, oncology is a big focus and that is large part to a lot of recent genome sequencing efforts that have identified several different highly recurrent mutations in genes encoding epigenetic proteins. These findings suggest a rational approach to design specific drugs that target these proteins in patient subsets that have these mutations...

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8. newbie on January 18, 2012 12:25 PM writes...

I'm new to the drug discovery field and I'm just curious... did these types of chromatin modifying enzymes (HATs, HDACs, HMTs, etc.) use to be considered "undruggable"? Does anyone know of a good reference on the whole "undruggable" concept? Thanks.

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9. K the Knight on January 18, 2012 12:31 PM writes...

This will be an exciting field for medicinal chemists in the future. Thanks to the private-public consortium SGC (Structural Genomics Consortium)and many small (and some large) companies there are already a lot of protein structures of the epigenetic players and small molecule probes. It is encouraging to see small molecules effectively inhibiting the protein-protein interaction of bromodomains and acetyl-lysine containg histones or proteins and change cellular processes. The epigenetic machinery is crucial for cellular responses to every kind of stress, internal or environmental, which might lead to disease manifesting over time. To extend the scope of epigenetic field we have to learn how to get cell-speficity besides target-selectivity, safety (even for the next generation?) will always be a concern in non-oncology indications. Another book out there is "The Epigenetics Revolution" by Nessa Carey (formerly CellCentric, now Pfizer-ed), those interested in scientifc history (and fraud?) should read A. Vargas, Journal of Exp. Zoology 312B, 667 (2009) : "Did Paul Kammerer discover epigenetic inheritance? A modern look at the controversial midwife toad experiments".

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10. Amused on January 18, 2012 6:05 PM writes...

Please tell me the drugs were we actually do have some sort of deeper understanding of the domino effects downstream of the target. As for the epigenetics buffs, anything that nowadays alters chromatin activity states is defined as being epigenetics leaving....There is no value left in the name epigenetics and it has been completely decoupled from the biology it once described.

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11. Anonymous on January 18, 2012 6:27 PM writes...

Managers on the rise in the Pharma industry need a new 'we've got to be in there' approach every year to impress the executive. Epigenetics was hot, the SGC (a bunch of crystallographers looking for something to 'nucleate' around (had to be soluble ie enzymes) and turn in to something big) get some money and then it is all hype, hype, hype. The conference industry picks up on it and organises some events 'somewhere nice' and advertises well - the snowball is rolling. This area will quietly recede (it will not be the next big thing) and the next 'hot area' of Life Science will come along ad nauseam. Promotions for all involved!

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12. Anonymous on January 18, 2012 8:23 PM writes...

Does drug discovery management and it's investors have the patience to see this through?? It's going to take some time and as we all know, "time is money". How much time/money are they willing to invest before walking away? I hope it's not another "fail fast" approach as we see in big pharma as they frantically try to find "something" of value.

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13. Ricardo Ros on January 19, 2012 2:08 AM writes...

The only value I see traditional med chem adding in epigenetics is to creating chemical probes, aiming for anything higher than this means you are managing the expectations of those above you poorly.

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14. HFM on January 19, 2012 4:48 AM writes...

As I understand it, the best clinical results have come from using these things in combination - scrambling the regulatory apparatus keeps the cancer cell from switching itself into a chemo-resistant state, so it has to actually mutate its DNA in order to get around the drug.

It's a bit like programming a computer with a kitchen magnet...but we're not long on better ideas.

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15. AML on January 19, 2012 5:41 AM writes...

It would be interesting to read your post on the article

In a recent article in the Journal of Computer-Aided Molecular Design, chemists Mark A. Murcko and W. Patrick Walters make their predictions for the year 2037 in the form of a piece of fiction about a beleaguered future drug hunter

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