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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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March 18, 2014

Another DNA-Barcoded Program From GSK

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Posted by Derek

Two more papers have emerged from GSK using their DNA-encoded library platform. I'm always interested to see how this might be working out. One paper is on compounds for the tuberculosis target InhA, and the other is aimed at a lymphocyte protein-protein target, LFA-1. (I've written about this sort of thing previously here, here, and here).

Both of these have some interesting points - I'll cover the LFA-1 work in another post, though. InhA, for its part, is the target of the well-known tuberculosis drug isoniazid, and it has had (as you'd imagine) a good amount of attention over the years, especially since it's not the cleanest drug in the world (although it sure beats having tuberculosis). It's known to be a prodrug for the real active species, and there are also some nasty resistant strains out there, so there's certainly room for something better.
InhA.png
In this case, the GSK group apparently screened several of their DNA-encoded libraries against the target, but the paper only details what happened with one of them, the aminoproline scaffold shown. That would seem to be a pretty reasonable core, but it was one of 22 diamino acids in the library. R1 was 855 different reactants (amide formation, reductive amination, sulfonamides, ureas), and R2 was 857 of the same sorts of things, giving you, theoretically, a library of over 16 million compounds. (If you totaled up the number across the other DNA-encoded libraries, I wonder how many compounds this target saw in total?) Synthesizing a series of hits from this group off the DNA bar codes seems to have worked well, with one compound hitting in the tens of nanomolar range. (The success rate of this step is one of the things that those of us who haven't tried this technique are very interested in hearing about).
InhA2.png
They even pulled out an InhA crystal structure with the compound shown, which really makes this one sound like a poster-child example of the whole technique (and might well be why we're reading about it in J. Med. Chem.) The main thing not to like about the structure is that it has three amides in it, but this is why one runs PK experiments, to see if having three amides is going to be a problem or not. A look at metabolic stability showed that it probably wasn't a bad starting point. Modifying those three regions gave them a glycine methyl ester at P1, which had better potency in both enzyme and cell assays. When you read through the paper, though, it appears that the team eventually had cause to regret having pursued it. A methyl ester is always under suspicion, and in this case it was justified: it wasn't stable under real-world conditions, and every attempt to modify it led to unacceptable losses in activity. It looks like they spent quite a bit of time trying to hang on to it, only to have to give up on it anyway.

In the end, the aminoproline in the middle was still intact (messing with it turned out to be a bad idea). The benzofuran was still there (nothing else was better). The pyrazole had extended from an N-methyl to an N-ethyl (nothing else was better there, either), and the P1 group was now a plain primary amide. A lot of med-chem programs work out like that - you go all around the barn and through the woods, emerging covered with mud and thorns only to find your best compound about fifteen feet away from where you started.

That compound, 65 in the paper, showed clean preliminary tox, along with good PK, potency, and selectivity. In vitro against the bacteria, it worked about as well as the fluoroquinolone moxifloxacin, which is a good level to hit. Unfortunately, when it was tried out in an actual mouse TB infection model, it did basically nothing at all. This, no doubt, is another reason that we're reading about this in J. Med. Chem.. When you read a paper from an industrial group in that journal, you're either visiting a museum or a mausoleum.

That final assay must have been a nasty moment for everyone, and you get the impression that there's still not an explanation for this major disconnect. It's hard to say if they saw it coming - had other compounds been in before, or did the team just save this assay for last and cross their fingers? But either way, the result isn't the fault of the DNA-encoded assay that provided the starting series - that, in this case, seems to have worked exactly as it was supposed to, and up to the infectious animal model study, everything looked pretty good.

Comments (24) + TrackBacks (0) | Category: Chemical Biology | Drug Assays | Infectious Diseases


COMMENTS

1. pinkerton on March 18, 2014 9:30 AM writes...

Derek, you might also want to take a look at this paper reporting allosteric phosphatase inhibitors discovered from a DNA-encoded library. Interestingly, they show a side-by-side comparison of the DEL hit with and HTS hit.

Nature Chemical Biology 10, 181–187 (2014)

Permalink to Comment

2. In Vivo Veritas on March 18, 2014 9:47 AM writes...

In vivo, veritas indeed. As a big pharma in vivo guy with a handful of J. Med. Chem papers, I found this quote:
" When you read a paper from an industrial group in that journal, you're either visiting a museum or a mausoleum." to be both amusing and all too true......

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3. annon too on March 18, 2014 10:04 AM writes...

"This, no doubt, is another reason that we're reading about this in J. Med. Chem.. When you read a paper from an industrial group in that journal, you're either visiting a museum or a mausoleum."

For GSK, absolutely true. The example shows the liability of such libraries, independent of how the compounds are identified or deconvoluted. The types of reactions used & allowed to constructed such libraries is very limited, as pointed out by Derek with the three amides. To remove them and make the "hit" a true drug candidate is daunting to the 10th degree.

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4. noname on March 18, 2014 10:20 AM writes...

#3: Dude, you totally missed the point. The library delivered compounds with good biochemical potency, cell activity, and decent PK. How does that show the liability of libraries of this type? I don't see how you can ascribe the lack of efficacy in the animal model on the library.

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5. barry on March 18, 2014 10:31 AM writes...

wow, these DNA-encoded libraries were the hottest new thing around 1996. Cool to see that someone made it work. But we don't get to know how long the project has been dead by the time it's published in J. Med. Chem. Not just the particular anti-TB drug candidate, but the whole discovery platform could be history by the time we get to see it in the "museum"

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6. annon too on March 18, 2014 10:33 AM writes...

4: Here's the points: Yes it's cute and clever technology that GSK spent a lot of money to obtain.

But, for GSK, in the business to deliver new drugs to the world, clever technology, per se, is not their remit. If the compounds in the libraries are not going to provide suitable leads that can actually deliver an NCE, then the whole thing is only an academic exercise of self-gratification. GSK is getting very good at this.

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7. PhenoScreen on March 18, 2014 10:49 AM writes...

#6 For your information GSK are doing very well at delivering new drugs to the world. In fact, by almost any metric, they are doing better than their peers. There has been a drip-drip of good news recently, just check out their injectable IL-5 phIII drug mepolizumab. GSK's leadership fully appreciate the potential of bleeding-edge science to deliver novel medicines for unmet medical need. To this end, they have been very bold in their acquisition of both scientific talent and new technologies. In fact, they have excelled at combining the best of the old paradigms with the best of the new!

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8. annon 3 on March 18, 2014 10:50 AM writes...

#6: If the technology is not providing suitable leads, then why are all these other med chemists pursuing these leads?? There's 3 different papers here. I don't understand. Are the GSK med chemists a bunch of fools? Why are they making analogs of cmpds if YOU KNOW they are hopeless?

Permalink to Comment

9. annon too on March 18, 2014 11:18 AM writes...

#7, 8: One simple question: what new drugs have come from this technology's leads? Very simple.

I can tell you, for sure, that any of the new drugs coming from GSK did not derive from this technology.

Further, is GSK is doing so well, why is the stock price still so stuck, not even having reached the same price as after the GW SB merger?

Permalink to Comment

10. annon 3 on March 18, 2014 11:31 AM writes...

#9. How long has GSK been running this program? The earliest paper would suggest since ~2010? How many new drugs has GSK discovered from HTS programs initiated since 2009? That would be 3 years from hit ID to drug. My guess is zero. There must be a better metric. You make no sense.

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11. barry on March 18, 2014 12:19 PM writes...

#10 the lag between research and publication in Pharma is routinely a decade or more. To note that the first paper is 2010 is to say nothing about how long the effort has been running

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12. daen on March 18, 2014 12:58 PM writes...

I used to work for Nuevolution in Copenhagen. The company developed a similar technology back in 2001, commercialized it in 2003, and has been quietly toiling away doing contract work for the likes of Merck and Novartis for over a decade. Without giving too much away, the amide-y flavour of the products was a problem that Nuevo solved fairly early on, and they have a broad palette of (non-amide) attachment chemistries that they developed (and probably even more since I left in 2007).

Permalink to Comment

13. The Aqueous Layer on March 18, 2014 1:45 PM writes...

#10 the lag between research and publication in Pharma is routinely a decade or more. To note that the first paper is 2010 is to say nothing about how long the effort has been running

Depends on where you work and how advanced the project was. It's not unheard of for this lag to be closer to 5 years on a project that died somewhere prior to clinical development, like this project was.

Also, given the higher profile nature of this project, they may have wanted to put it out there in a more rapid fashion after its death.

Permalink to Comment

14. LeeH on March 18, 2014 3:34 PM writes...

An example of not worrying about the properties of the leads that you could end up with. High MW for a lead (437.5), not much room to maneuver. Ditto for PSA (109.5) - a consequence largely of all of the amides (90 units just from the 3 carbonyls).

Permalink to Comment

15. certainly not agilast on March 18, 2014 4:04 PM writes...

I'm waiting on the GSK 2104 pipeline update with interest. My rough guess is 8 new Phase 1 starts from the much lauded new R organisation in 2013-4. Not enough to refill the pipeline ....

The IL-5 Ab has a SB code and was first in Phase 3 in 2006 - so much for a 10 year lag time

Permalink to Comment

16. watcher on March 18, 2014 5:25 PM writes...

#15: Good luck on that 2104 GSK pipeline.

Their IL-5-Ab is at least 12 years old. It sat on the shelf for a number of years, before being resurrected & "rebranded".

Permalink to Comment

17. Nick K on March 19, 2014 5:45 AM writes...

#7 PhenoScreen (or may I call you Agilist?): The GSK share is exactly back to where it was in 1998 - sixteen years ago. If the company is doing as well as you say, why is this?

We all miss your usual references to "Andrew", "Patrick", and "Moncef".

Permalink to Comment

18. PhenoScreen on March 19, 2014 8:20 AM writes...

In answer to #17, regarding share price, 1998 was a high-water mark for stocks generally (pre-dotcom and all that). A more meaningful comparison for GSK would be the last six years, a period that coincides with Sir Andrew's tenure. That tells quite a positive story and amply vindicates the tough decisions that were taken to re-boot R&D

Permalink to Comment

19. watcher on March 19, 2014 10:31 AM writes...

18: The reasons that GSK stock has increased since Sir Andy is simply due to compounds that were already in the pipeline, discovered and put into full development BEFORE his time in the big chair. There is no denying this, no matter how hard to try to repackage Sir Andy. What has Sir Andy done? Well, he authorized buying Sirtris and HGS, neither deals will ever make back the amount that was spent on them. He has invested in China, which led to at least two investigations by China or GSK itself, he has continued to downsize GSK research staff, and he has continued to take home a nice chunk of change in yearly compensation. The stock price at the time of the GW and SB merger in 2001 was over 60. That would be the only fair comparison, not a price before that date, and has not seen that level in years. So, why is it that it deserves your defensive accolades?

Permalink to Comment

20. PhenoScreen on March 19, 2014 12:15 PM writes...

#19 Watcher - I assume you're a former GSK employee who left some time ago?

Permalink to Comment

21. Hap on March 19, 2014 12:36 PM writes...

1) Isn't it sort of funny how many of those unhappy GSK ex-employees there are? Wonder how that happened...

2) In moderation : GSK's stock maxed in 2000-1 and is nowhere near even its 1998 level. It's gone up a lot since the bottom in 2008, but so has (almost) everything else. I don't know how GSK has done relative to other pharmas since 2008; it certainly hasn't kept up with the FTSE over that time (the FTSE is at its pre-2008 peak level, while GSK is...not).

Of course, you really want to look at long-term production, which you won't see for a while, and which is difficult to connect with a single person in any case. Probably why so many CEOs manage to keep lucrative positions while their company languishes in the doldrums or circles the drain too slowly to be yet noticed, while their employees get the ax.

Permalink to Comment

22. watcher on March 19, 2014 5:28 PM writes...

20 PhenoScreen: What does it matter if I would be, was or never work(ed) at GSK. When actual facts, events, activities are accurate, the history of employment does not matter when truthfully, ethically, and honestly presented.

Permalink to Comment

23. Nick K on March 19, 2014 11:40 PM writes...

PhenoScreen: Touched a nerve, have I?

#22 Watcher: PhenoScreen (aka Agilist, OpentoInnovation and other pseudonyms) is an incompetent PR flack who pops up every time GSK is mentioned on the Pipeline to offer gushing praise of the firm's senior management.

Permalink to Comment

24. Anonymous on April 8, 2014 7:51 AM writes...

So, what about the promised post on the LFA-1 paper, coming soon?

Permalink to Comment

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