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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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April 6, 2012

Europe Wants Some of That Molecular Library Action

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Posted by Derek

We've talked about the NIH's Molecular Libraries Initiative here a few times, mostly in the context of whether it reached its goals, and what might happen now that it looks as if it might go away completely. Does make this item a little surprising?

Almost a decade ago, the US National Institutes of Health kicked off its Molecular Libraries Initiative to provide academic researchers with access to the high-throughput screening tools needed to identify new therapeutic compounds. Europe now seems keen on catching up.

Last month, the Innovative Medicines Initiative (IMI), a €2 billion ($2.6 billion) Brussels-based partnership between the European Commission and the European Federation of Pharmaceutical Industries and Associations (EFPIA), invited proposals to build a molecular screening facility for drug discovery in Europe that will combine the inquisitiveness of academic scientists with industry know-how. The IMI's call for tenders says the facility will counter “fragmentation” between these sectors.

I can definitely see the worth in that part of the initiative. Done properly, Screening Is Good. But they'll have to work carefully to make sure that their compound collection is worth screening, and to format the assays so that the results are worth looking at. Both those processes (library generation and high-throughput screening) are susceptible (are they ever) to "garbage in, garbage out" factors, and it's easy to kid yourself into thinking that you're doing something worthwhile just because you're staying so busy and you have so many compounds.

There's another part of this announcement that worries me a bit, though. Try this on for size:

Major pharmaceutical companies have more experience with high-throughput screening than do most academic institutes. Yet companies often limit tests of their closely held candidate chemicals to a fraction of potential disease targets. By pooling chemical libraries and screening against a more diverse set of targets—and identifying more molecular interactions—both academics and pharmaceutical companies stand to gain, says Hugh Laverty, an IMI project manager.

Well, sure, as I said above, Screening Is Good, when it's done right, and we do indeed stand to learn things we didn't know before. But is it really true that we in the industry only look at a "fraction of potential disease targets"? This sounds like someone who's keen to go after a lot of the tough ones; the protein-protein interactions, protein-nucleic acid interactions, and even further afield. Actually, I'd encourage these people to go for it - but with eyes open and brain engaged. The reason that we don't screen against such things as often is that hit rates tend to be very, very low, and even those are full of false positives and noise. In fact, for many of these things, "very, very low" is not distinguishable from "zero". Of course, in theory you just need one good hit, which is why I'm still encouraging people to take a crack. But you should do so knowing the odds, and be ready to give your results some serious scrutiny. If you think that there must be thousands of great things out there that the drug companies are just too lazy (or blinded by the thought of quick profits elsewhere) to pursue, you're not thinking this through well enough.

You might say that what these efforts are looking for are tool compounds, not drug candidates. And I think that's fine; tool compounds are valuable. But if you read that news link in the first paragraph, you'll see that they're already talking about how to manage milestone payments and the like. That makes me think that someone, at any rate, is imagining finding valuable drug candidates from this effort. The problem with that is that if you're screening all the thousands of drug targets that the companies are ignoring, you're by definition working with targets that aren't very validated. So any hits that you do find (and there may not be many, as said above) will still be against something that has a lot of work yet to be done on it. It's a bit early to be wondering how to distribute the cash rewards.

And if you're screening against validated targets, the set of those that don't have any good chemical matter against them already is smaller (and it's smaller for a reason). It's not that there aren't any, though: I'd nominate PTP1B as a well-defined enzymatic target that's just waiting for a good inhibitor to come along to see if it performs as well in humans as it does in, say, knockout mice. (It's both a metabolic target and a potential cancer target as well). Various compounds have been advanced over the years, but it's safe to say that they've been (for the most part) quite ugly and not as selective as they could have been. People are still whacking away at the target.

So any insight into decent-looking selective phosphatase inhibitors would be most welcome. And most unlikely, damn it all, but all great drug ideas are most unlikely. The people putting this initiative together will have a lot to balance.

Comments (20) + TrackBacks (0) | Category: Academia (vs. Industry) | Biological News | Drug Assays


COMMENTS

1. SP on April 6, 2012 9:04 AM writes...

Some of this is just a chance for pharma to unload their closed sites onto the government and get credit for an "in-kind" payment for something they weren't going to use anyway.

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2. Rick Wobbe on April 6, 2012 9:46 AM writes...

Is it wise to frame our decision about the value of such libraries strictly in terms of their use as sources for drug candidates, leads or even hits? Perhaps they have broader, equally impact-full value in their use as probes of biological function, which touches not just drug discovery but fields upon which drug discovery critically depends, including toxicology, cell biology, physiology and neurobiology to name just a few. Issues like solubility, promiscuity of action, chemical tractability and biological potency affect these libraries, but many of these items are less problematic for basic research than they are in drug discovery. Chemical inhibitors have offered huge value as complements to genetic and biochemical tools for dissecting and understanding biological pathways. What's the opportunity cost, even within the drug R&D industry, if these libraries go away, as Derek says, because they don't meet the stringent criteria of a drug lead? I think we have no idea because we haven't thought of it that way enough.

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3. PharmaHeretic on April 6, 2012 9:48 AM writes...

Any comments?
----

Pfizer to Trim Fired Workers’ Benefits to Reduce Costs

http://www.bloomberg.com/news/2012-04-05/pfizer-to-cut-benefits-for-fired-workers-as-company-trims-costs.html

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4. dvizard on April 6, 2012 10:38 AM writes...

"that will combine the inquisitiveness of academic scientists with industry know-how."

Like scientists in industry are somehow not "inquisitive" enough?

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5. Anonymous on April 6, 2012 11:59 AM writes...

If you think that there must be thousands of great things out there that the drug companies are just too lazy (or blinded by the thought of quick profits elsewhere) to pursue, you're not thinking this through well enough.

People are supposed to think things through? Since when?

It's a bit early to be wondering how to distribute the cash rewards.

I don't think anyone on either the pharma or academic side ever believes it's too early to start talking about when and how much they stand to make. At least they never act like it.

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6. Christophe Verlinde on April 6, 2012 2:29 PM writes...

Well done HTS is very valuable (see e.g. "Impact of high-throughput screening in biomedical research" (2012)
Nature Rev. Drug Disc. 10:188-195). However, the queues for HTS screening at NIH sponsored facilities
can be quite long. Even AFTER all the quirks of the assay have been worked out and test runs
with limited test collections demonstrate a good Z', it is not uncommon to have to wait another NINE
months before the HTS is carried out.

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7. Anonymous on April 6, 2012 5:33 PM writes...

"it's easy to kid yourself into thinking that you're doing something worthwhile just because you're staying so busy and you have so many compounds."

Couldn't help LOL at the above paragraph, it is very true.

And this is also true: "it's easy to kid yourself into thinking that you're doing something worthwhile just because you're staying so busy and you have so many meetings."

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8. Hopeless on April 6, 2012 6:10 PM writes...

It would have a profound impact on medical research in future. Most of targets were discovered and studied first in academia, now they could have tool compounds to play, in stead of being limited to doing knockouts and knockins. It could also avoid redundancy of expensive HT screening against the same targets in Pharmas, if multiple hits were reported in literature. So Pharma could benefit tremendously from the next wave of new targets. The problem I forsee is not everyone is angel in academia. Pharma might have to pay for some useless high nicromolar fake hits.

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9. HTSguy on April 6, 2012 6:14 PM writes...

@4: "Like scientists in industry are somehow not "inquisitive" enough?"

As an academic and former Pharma HTS leader, I have to say that the motivations are just very different. In industry you're trying to efficiently (we hope) find a drug. In academia, they are looking for something (anything?) new. None of the projects I've seen in academia work on the usual Pharma targets. Almost all are phenotypic assays. They have some data to support them, but are a very long way from "clinically validated". In fact, most VP's Research or VCs wouldn't go within a mile of them. Even a modestly potent, reversible, and reasonably soluble compound is often sufficient to test a hypothesis in vivo (yes, I know about PK, although it's amazing what you can do with an Alzet pump if the compound is sufficiently soluble).

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10. anonie on April 6, 2012 6:47 PM writes...

Too many "scientists" think that good, productive, forward moving work is defined and validated when one is "busy being busy". Not.

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11. cdsouthan on April 7, 2012 2:49 AM writes...

As I posed in a question at the conclusion of the recent IMI webcast its easy to get confused between the above and EU OPENSCREEN http://www.eu-openscreen.de/, particularly as both seem to be getting EU finding. Part of the answer was that IMI structures and data would stay blinded to outsiders whereas the latter will be, be definition "open". It might be useful for the parties concerned to jointly clarify the similarities and differences

Permalink to Comment

12. AnotherHTSguy on April 7, 2012 11:24 AM writes...

@2, and also @6:

I'll believe that academics can do a good job of HTS, but not until they've spent 15 years re-inventing everything it's taken industry that long to learn. I doubt very much that they'll believe there's much they can learn from the experience of others, or that they'll do proper rigorous mode of action on the hits.

Having worked up HTS hits into leads, and listened to what senior academics think HTS is, there's a lot of naivety combined with arrogance to overcome, and that's not a good combination. I've tried explaining that 99% of HTS hits are fluorescent, light-scattering, aggregating, metal-binding, plastic plate-binding, irreversible, poly-stoichiometric artefacts, and their eyes just glaze over with a pitying look, because that doesn't fit with their idealized, theoretical preconceptions of how drug discovery works. Nor are they interested in hard work such as the graft needed to find the one or two true hits that might be buried somewhere within the pile of crud, because that's not very intellectual and therefore beneath them.

Good scientists are going to end up wasting their time on junk compounds with no value for basic research. And make no mistake, the sheer numbers involved mean that a few of those also do soemthing to cells, just not via the intended target. Those will get published, because these guys all review each others' papers and none of them understands how to validate hits properly, and the literature will get even more polluted with dodgy compounds than it already is.

Obviously there are a few academics out there who get it, Brian Shoichet being one who comes to mind, but others are pretty slow on the uptake I'm afraid.

Permalink to Comment

13. MoMo on April 8, 2012 2:21 PM writes...

"99% of HTS hits are fluorescent, light-scattering, aggregating, metal-binding, plastic plate-binding, irreversible, poly-stoichiometric artefacts"

--another HTS guy

"Every molecule should be tested by dynamic light scattering first then for non-specific membrane FX and perturbation second--only then is it suitable for my assays"

---Grandma MoMo, sitting on her porch with me as a child, in the backwoods of Tennesee

Permalink to Comment

14. CR on April 9, 2012 7:30 AM writes...

@dvizard #3:
"that will combine the inquisitiveness of academic scientists with industry know-how."

Like scientists in industry are somehow not "inquisitive" enough?

As a former Pharma scientist now in the academic world I have to agree with HTSguy (#9). Moreover, I would say academics are more inquisitive because they are allowed to be. Not that industry people are not inquisitive; but where do you find time/budget to follow through? It was very frustrating to have that mythical (10 - 15%) of your time for exploratory research in Pharma, but nobody actually did anything exploratory because it was never encouraged. In fact, it was discouraged more often than not.

I also have to agree with Rick (#2). People have to look at these endeavors as tool compound hunting, not drug hunting. If targets can be validated, then that is a success.

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15. Anonymous on April 11, 2012 4:41 AM writes...

@12 I agree with your comments.

I would also add this approach has been tried within some drug companies. What it led to was a load of weak hits that no-one wanted to do anything with. So then some chem teams were applied and turned the weak hits into some useful leads (ie cmpds that you could do some reasonable CIR work with). However, this was expensive and slow and will be the reason why this IMI initiative fails. No-one will actually take on the cost of doing something to the hits to turn them into something useful unless the target is really hot - then it will happen anyhow so what is the point of this.

This is a bad example of government funded science - someone wants to get some funding to do the stuff they like doing and hypes up all the future benefits - none of which will materialize.

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16. Rick Wobbe on April 11, 2012 8:09 AM writes...

Calling this "a bad example of government funded science" goes a step too far. It's fair game to criticize the extent to which the work may be overhyped and the utility of the subject compounds as drug leads, but to imply the work is a waste of research finding because it doesn't fit your notion of a commercializability is wielding a Birmingham screwdriver with a bit too much abandon. it gives me flashbacks to the excesses of John Dingell and William Proxmire's efforts to ensure govt-funded research was "useful". By this logic, one could construe work on alpha-amanitin and cycloheximide as bad examples of government funded science, which I hope none of us would do.

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17. Anonymous on April 12, 2012 6:27 AM writes...

@16 I do claim it will be a waste because it has been tried before - and failed. I don't think you can judge what will be 'useful' but you can spot what will 'not be useful' - and repeating others mistakes falls into that category. The definition of madness and all that....

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18. Claire on April 12, 2012 6:30 AM writes...

"The reason that we don't screen against such things as often is that hit rates tend to be very, very low, and even those are full of false positives and noise."

I don't think industry has a particularly good record of dealing with weeding out false positives, especially for targets where the hit rate is low. This is possibly a hangover from the ATP binder / kinase target days where chemists can spot the real hits by eye and ignore the rest.

If you look in the literature there is a large gap (with an honourable mention to Brian Shoichet’s lab and a Novartis ratio test paper) where all the ‘best method of identifying false positives across large datasets’ papers should be.

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19. Innovorich on April 12, 2012 8:12 AM writes...

"they're already talking about how to manage milestone payments and the like. That makes me think that someone, at any rate, is imagining finding valuable drug candidates from this effort."

Well that's mostly because IMI want the program to be sustainable after 5 years so you need a way of someone wanting to fund the outcomes and if they can't own it, they won't.

The other thing is that a large part of the library is intended to come from academics, in terms of novel scaffolds/libraries. To make this a reality, there has to be an incentive, that makes sense financially and legally, for them to give up their great compound ideas.

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20. Rick Wobbe on April 12, 2012 8:19 AM writes...

#17, I definitely take your point about madness of repeating the same thing, hoping for a different outcome, IF the "same thing" is expecting such initiatives to yield drug leads, which does seem to be asking for too much. (although history shows that non-industrial screening has made significant contributions to finding novel drug classes) However, for a more fundamental endeavor - identifying and characterizing chemical probes that affect biological systems in interesting and useful ways - I do not see how it can be called a failure (whatever that means). I believe that eliminating these libraries and testing programs would be a loss to basic research and, ultimately, drug discovery.

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