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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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October 21, 2011

Does Anyone Want the NIH's Drug Screening Program?

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Posted by Derek

Science is reporting some problems with the NIH's drug screening efforts:

A $70-million-a-year program launched 7 years ago at the National Institutes of Health (NIH) to help academic researchers move into industry-style drug discovery may soon be forced to scale back sharply. NIH Director Francis Collins has been one of its biggest champions. But the NIH Molecular Libraries, according to plan, must be weaned starting next year from the NIH director's office Common Fund and find support at other NIH institutes. In a time of tight budgets, nobody wants it.

The fate of the Molecular Libraries program became “an extremely sensitive political issue” earlier this year when NIH realized it would not be easy to find a new home for the program, said one NIH official speaking on background. . .

. . .John Reed, head of the Sanford-Burnham Medical Research Institute screening center in San Diego, which receives about $16 million a year from the Common Fund, says his center has so far attracted only modest funding from drug companies. He expressed frustration with the Common Fund process. “NIH has put a huge investment into [the Molecular Libraries], and it's running very well,” he says. “If there's not a long-term commitment to keep it available to the academic community, why did we make this hundreds of millions of dollars investment?”

Good question! This all grew out of the 2003 "NIH Roadmap" initiative - here's a press release from better days. But it looks partly to be a victim of sheer bad timing. There's not a lot of extra money sloshing around the drug industry these days, and there sure isn't a lot in NIH's budget, either. You wouldn't know that there's a problem at all from looking at the program's web site, would you?

Since I know there are readers out there from both sides of this particular fence, I'd be interesting in hearing some comments. Has the screening initiative been worthwhile? Should it be kept up - and if so, how?

Comments (21) + TrackBacks (0) | Category: Academia (vs. Industry) | Drug Assays


COMMENTS

1. pharmadude on October 21, 2011 12:10 PM writes...

HTS is one of the least innovative aspects of big pharma drug discovery. I would think academia and the government would pursue more intellectual projects.

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2. lynn on October 21, 2011 12:31 PM writes...

Well, here's a paper illustrating one of the problems of the NIH library/ies: Babaoglu et al. 2008. Comprehensive Mechanistic Analysis of Hits from High-Throughput and Docking Screens against β-Lactamase. Journal of Medicinal Chemistry 51:2502-2511. Lots of garbage in the library. While there have been problems in selecting targets for screening, and [I would say] the robustness of screens, HTS is only as good as the libraries.

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3. MolecularGeek on October 21, 2011 1:01 PM writes...

Politically, I am sure that Francis Collins and the rest of the leadership at NIH feel that translational research is not an optional component in their portfolio. The majority of people I know who are not part of the pharmaceutico-medical complex think that their drug costs are too high. Cutting one of the programs that is supposed to encourage new drug development at lower industrial costs would not sell right now. I don't know how much MLRI actually does lower costs, but like being forced to take off your shoes at the airport, it's a bit of theatre that convinces people that the government is trying to solve a problem that the population cares about.

From a purely academic standpoint, the program has been a qualified success. The amount of biological and chemical data that has been added to pubchem, and that is programmatically accessible over the internet is, for someone who remembers QSAR series of 10-15 compounds, a huge break with the past. Without PubChem (and ChemBL), the majority of my development work would be painful, if not impossible. Similarly, while one can argue with the quality of the screening libraries, and the robustness of the assays, it isn't at all clear that academic labs that wanted or needed to work with HTS technologies would have any other viable options. I can't imagine one's favorite CRO in Shanghai or Mumbai being eager to run a custom assay or a custom library screen at the rates MLRI offers on the small-scale problems that most academic groups would have.

This is not to say that the program doesn't have problems. The assays, as mentioned, need further development to improve their reliability, and the data coming out of pubchem is painfully raw data, requiring careful curation and validation. But I wouldn't want to give it up, either.

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4. yes but on October 21, 2011 1:30 PM writes...

I suspect that MLRI makes drug discovery more expensive rather than less, once government spending is included. As #1 suggests, pharma has spent decades doing HTS and making sure it's efficient. The price of a screen is nothing next to what it costs post-candidate selection when the MDs start to take their cut.

Genuine questions: how many academics have the time, the inclination or the experience to turn their assay into one that's truly fit for HTS? We seem to have a hard enough time with that in industry.

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5. Lester Freamon on October 21, 2011 2:51 PM writes...

$70 Million a year is a pretty good deal for what we should have been able to get out of this program, which is ~25 new, moderately drug-like compounds against previously unscreened targets. This program could be a way to simply map the druggable-but-yet-undrugged proteome and get new lead molecules into animal models (or at least give a scaffold for some development if someone wants to sink a few million into medicinal chemistry to get a better version).

The problem was that the program focused too much on quantity over quality--the screening centers were graded/funded solely on the number of "probes" meeting original criteria (Usually IC50 cutoffs and an antitarget) and not on the quality of what was produced. As such, far too many shitty screens were approved--funding for RO3's for this project was near the 50-percent level. A more focused program, with more intensive medicinal chemistry and money for contract work on ADMET type assays would have been better.

In addition it would have been nice to have some screening library curation such as to remove compounds like this...
http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?sid=26725212

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6. MolecularGeek on October 21, 2011 5:52 PM writes...

I'll concede that that aza-tropenone isn't a very nice looking compound, but it isn't as if the MLRN libraries brought it in from thin air. It appears to have been part of the NCI screening library, and it's stable enough to have been included in a couple of manual screens. One of them even used a series of conjugated tropenones to look for anti-inflamatory activity.

Is there a reason that you're picking on that one compound in particular as being a bad component of the library?

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7. anon 1 on October 21, 2011 5:54 PM writes...

In vogue and sexy at the time, but not something that NIH should ever have done. Waste of time, money, resource, and not their reason to exist.

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8. Nev Telen on October 21, 2011 6:58 PM writes...

A major problem with the Molecular Libraries program is that it was too large. The large size ($70M to $100M) makes it almost impossible for other institute and centers to "adopt" the program upon the wind down of the Common Fund support. I had heard that attempts were made to scale back the program at several stages but these were resisted primarily by Francis Collins. Furthermore, the output from the program (in terms of validated probes) does not seem commensurate with the large expenditure.

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9. JB on October 21, 2011 7:23 PM writes...

A lot of the data available is 6 to 12 months behind due to embargoes for IP and publication reasons. Starting in 2009-2010 fiscal year of the program, much more QC was instated, with an outside review panel reviewing the reports prior to acceptance and publication. Together that mean that a lot of much better more recent stuff is just starting to come out of the network. Furthermore, I believe (not sure) the $70M/year is only the production phase that started in 2008, not the entire 7 year program. So at the end there should be an accounting- for, say, $500M of funding what came out the other end? One clinical candidate so far, several other pre-clinical programs, a lot of tool compounds, a ton of public data; then compare that return to R&D returns from pharma.

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10. Anonymous on October 22, 2011 12:32 PM writes...

@#7 Exactly. And if the guvment and society want to control drug prices, they first need to control Wall Street. Runaway health care costs are the result of runaway expectations for financial return.

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11. Jim H on October 22, 2011 2:49 PM writes...

Silly academic elitists. Drug companies control drug prices because they are much more efficient and effective than bureaucratic boondoggles like the NIH, who would rather usurp our tax money and cram it in their pockets.

I recently dismantled a HTS lab system in PA with fully robotic and automated cell culture through test compound application and analysis system. It paid for itself in 5 years. Can the NIH say the same? We need to cut NIH funding, now.

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12. mjay on October 23, 2011 4:08 PM writes...

Good luck trying to find an Armani suit at the Filene's Basement "everything must go" sale...

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13. Anonymous on October 23, 2011 10:15 PM writes...

What is going on with the national center for the advancement of translational sciences (NCATS) that was in the news last year and was supposed to be up and running Oct.1/2011. Was the NIH screening program supposed to be part of it? I guess the whole thing is on hold?

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14. Lars on October 24, 2011 12:17 AM writes...

Noone would even dream of expecting that a bigpharma (or a smaller biotech for that matter) would deliver anything concrete within the frame of 7years from conception. The MLSCN etc has induced à major paradigm shift in academic research and surely, academia is going to take some time to adjust to the world of HTS.

Let's not forget that a large portion of the projects running through the NIH are not aimed at developing CDs but rather to develop cmpds that help increase the fundamental knowledge of putative drug targets. With that in mind, one should be humble in critique of the library content, although I agree that many of the cmpds in the library may cause more confusion than conclusion.

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15. Nuclear Option on October 24, 2011 5:32 AM writes...

I like this program and watched it improve quite a bit over the last few years. It has dramatically increased academic interest in pharmacology, chemical biology and drug discovery. This is a good thing considering the climate in industry. There is no doubt the index library has limitations, but could surely evolve like all industry decks. The screens run were in many caseshighky creative, and the assays were developed by true experts in the biology. All a good thing.

I also echo the above comment about probe deliverables. This was regrettable, as it is not realistic to think hit to lead can be centrralized in this way. The benchmark also encouraging the scientists to call compounds probes which surely do not meet acceptable criteria

Permalink to Comment

16. Nuclear Option on October 24, 2011 5:40 AM writes...

...darn iPad...

The benchmark also encourages scientists to identify compounds as probes which would not meet acceptable criteria.

Still, the program has merit. We conducted three screens, and are working up some scaffolds we would not have encountered otherwise. One additional project was inspired by a public, cell-based screening hit which we suspect operates against a compelling target.

So I hope they keep it open for business, but they can drop the lead optimization and chemical probe deliverables part. Perhaps make this a separate RFA, for promising projects among collaborating labs with specific and complementary expertise. Long term collaborations leveraging funds and resources develop between investigators, not with core labs.

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17. Anonymous on October 24, 2011 10:22 AM writes...

Um...
The few times I've looked at the results of these efforts, boondogle would be a kind adjective. A large number of the screens were retreads of old targets like monoamine receptors (Why?). There is also a tendency of the academic investigators to view hits as chemical probes despite the lack of specificity data, PK data, mechanistic data etc. I've reviewed quite a few grants of investigators eager to spend a lot of money doing in vivo mechanistic studies with poorly characterized screening hits. I'm all for translational research, but drug discovery doesn't mesh well with academic culture. Let's open up some of that funding for the small companies that are actually created for translational work.

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18. Zippy on October 24, 2011 11:53 AM writes...

I believe that the goal for the early Molecular Libraries efforts was to identify novel and useful pharmacological probe compounds, not necessarily drug candidates. Some good reasons exist to do this in an academic setting to complement pharma efforts. A secondary and later goal may be to build infrastructure and capabilities to enable drug discovery for interested academics.

The dominant reason for expensive failures in drug discovery is lack of efficacy in PII. This follows from inadequate understanding of the underlying biology. Target validation data best comes from human genetic studies and very solid pharmacology coupled with measurements in human tissues. Such data is often lacking for targets pursued at pharma. The Molecular Libraries program gives anyone that can write an R03 application the opportunity to generate pharmacological probes to test ideas about novel targets. These are often the people who know the most about the targets and biology. The idea is to improve to biological understanding, which can only aid drug discovery efforts. This approach is a bit like the tool compound for external use approach at many pharma, but on a larger scale and with input from academic labs. This would seem to be an opportunity for NIH-funded investigators to fulfill their mission to improve human health.

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19. Jonathan on October 24, 2011 12:07 PM writes...

@Jim H I am trying to stay polite so rather than insult you I will simply direct your attention to these pair of reports: http://www.genome.gov/27544383

When you can show me that you're generating a 141:1 ROI and that you've created as many jobs, and generated as much wealth, as NIH has recently, then I'll listen to your ideas.

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20. FarmaFan on October 24, 2011 9:44 PM writes...

Gumment run healthcare at it's best. We need much more of this; I can't wait for single-payer. Utopia is just around the corner.... or the edge of the cliff to utter misery.

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21. ty on October 25, 2011 3:49 PM writes...

I am with 18 followed by 17. The intention serves (served?) a very important bottleneck. However, as 17 pointed out, the cultures don't mesh very well. Sure, the library is filled with crap and the PIs don't know what they are doing with small molecules. But again, we won't go anywhere unless we fill the gap between biology and chemistry and cross the bridge between academia and industry. I think it's been a great learning process and should continue.

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