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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: derekb.lowe@gmail.com Twitter: Dereklowe

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In the Pipeline: Don't miss Derek Lowe's excellent commentary on drug discovery and the pharma industry in general at In the Pipeline

In the Pipeline

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March 27, 2013

The DNA-Encoded Library Platform Yields A Hit

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Posted by Derek

I wrote here about DNA-barcoding of huge (massively, crazily huge) combichem libraries, a technology that apparently works, although one can think of a lot of reasons why it shouldn't. This is something that GlaxoSmithKline bought by acquiring Praecis some years ago, and there are others working in the same space.

For outsiders, the question has long been "What's come out of this work?" And there is now at least one answer, published in a place where one might not notice it: this paper in Prostaglandins and Other Lipid Mediators. It's not a journal whose contents I regularly scan. But this is a paper from GSK on a soluble epoxide hydrolase inhibitor, and therein one finds:

sEH inhibitors were identified by screening large libraries of drug-like molecules, each attached to a DNA “bar code”, utilizing DNA-encoded library technology [10] developed by Praecis Pharmaceuticals, now part of GlaxoSmithKline. The initial hits were then synthesized off of DNA, and hit-to-lead chemistry was carried out to identify key features of the sEH pharmacophore. The lead series were then optimized for potency at the target, selectivity and developability parameters such as aqueous solubility and oral bioavailability, resulting in GSK2256294A. . .

That's the sum of the med-chem in the article, which certainly compresses things, and I hope that we see a more complete writeup at some point from a chemistry perspective. Looking at the structure, though, this is a triaminotriazine-derived compound (as in the earlier work linked to in the first paragraph), so yes, you apparently can get interesting leads that way. How different this compound is from the screening hit is a good question, but it's noteworthy that a diaminotriazine's worth of its heritage is still present. Perhaps we'll eventually see the results of the later-generation chemistry (non-triazine).

Comments (12) + TrackBacks (0) | Category: Chemical Biology | Chemical News | Drug Assays | Drug Development


COMMENTS

1. freddy on March 27, 2013 12:53 PM writes...

How many commenters were there in the last thread saying how triazines always had crappy PK properties, how they could never be drugs, etc.? I'm looking at you Glaxoid.

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2. archie on March 27, 2013 1:32 PM writes...

The question is why you need to screen a billion tri-substituted triazines to find one mono-substituted one? The combinatorics mean you'd only need to screen the cube-root of a billion, or 1000 smaller molecules, to reach the same end-point. For which DNA-encoded technology wouldn't be needed...

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3. weirdo on March 27, 2013 1:35 PM writes...

Isn't this what Ensemble is doing, too, just focused on macrocycles?

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4. Squib on March 27, 2013 1:46 PM writes...

Although a 1,2,4 not 1,3,5 triazine, Lamotrigine has decent PK properties and has been on the market for 20 years...

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5. freddy on March 27, 2013 1:50 PM writes...

Archie, if you go back and look at the synthetic scheme in the original 2009 paper, you'll realize that the sEH compound actually contains fragments from two cycles of chemistry, with 32 and 384 inputs respectively. So one would have needed to make something like 12K compounds to find this. Not impossible, but fairly resource intensive.

Actually the ability to discover sub-structures of the library products is explicitly mentioned in that paper and considered something of a feature rather than a bug. The reported ADAM_TS and MAPK inhibitors are also substructures, but with different truncation patterns than the sEH compound. They are more like 1 in a million shots.

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6. Anon on March 27, 2013 3:16 PM writes...

@3 Short answer, no.

How long for the med chem community to decide that high throughput sequencing has salvaged the concept of combi chem? 10 years? 20? Never? I'd say freddy is convinced. But he's probably employed doing it.

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7. Ubiquitous Anonymous on March 28, 2013 6:21 PM writes...

How many times do you have to execute a core switch to optimize PK anyway (2,3,4 times per series)? Who cares if it's a non-optimal core, you just cannot get this type of SAR directly from a screen using any other technology. I'm surprised it hasn't taken root everywhere by now.

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8. Ubiquitous Anonymous on March 28, 2013 6:22 PM writes...

How many times do you have to execute a core switch to optimize PK anyway (2,3,4 times per series)? Who cares if it's a non-optimal core, you just cannot get this type of SAR directly from a screen using any other technology. I'm surprised it hasn't taken root everywhere by now.

Permalink to Comment

9. Ubiquitous Anonymous on March 28, 2013 6:22 PM writes...

How many times do you have to execute a core switch to optimize PK anyway (2,3,4 times per series)? Who cares if it's a non-optimal core, you just cannot get this type of SAR directly from a screen using any other technology. I'm surprised it hasn't taken root everywhere by now.

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10. Steve Young on March 29, 2013 2:16 AM writes...

As with most things in life: You get out what you put in. If you put in a few hundred million triazines; surprise, surprise, they will be there in your hit list. If you put in drug-like/ lead-like compounds that's what you will find when you screen it. There are providers out there applying this strategy if you look.

Permalink to Comment

11. archie on March 30, 2013 12:39 PM writes...

@5: "one would have needed to make something like 12K compounds to find this"

Fair enough, but if you just purchased 12k compounds you'd stand a better chance of finding a hit, because by definition these would be more diverse than compounds made by any single chemistry.

For the examples where you require a core plus >2 cycles of chemistry, those compounds must be big. If you can chop them in half without losing all your potency, you wouldn't have needed them to be so big in the first place, and you could have screened a smaller library. Good luck to you, but I don't believe this makes sense as a way to find drugs.

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12. freddy on March 30, 2013 8:40 PM writes...

@11: "Fair enough, but if you just purchased 12k compounds you'd stand a better chance of finding a hit, because by definition these would be more diverse than compounds made by any single chemistry."

I agree 100 percent with that statement. Diverse purchased compounds will always have a higher hit rate than the same number of outputs from a single synthesis. The question is how much does it cost to purchase and screen those 12K compounds, compared to synthesize and screen an encoded library? Would you accept half the hit rate for one-tenth the cost?

To your next point, and it's a good one, I would just say that it is possible to make very large libraries with a lead-like property profile.


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