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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

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February 2, 2010

A Pile of Malaria Leads For the Taking

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Posted by Derek

I kept meaning to write last week about GlaxoSmithKline's decision to open up a database of possible lead compounds against malaria. These were hits from a larger screen that the company ran, and been made unusually public. (Here's the press release as a PDF). There are about 13,500 structures, apparently. The company is to be commended for doing this, naturally, but I wish that the press coverage would emphasize a few things that it hasn't so far.

For one, these are not antimalarial compounds, at least not to a medicinal chemist. Some of them might be, but for now, they're all potential antimalarials, with a long, long way to go. This is all in what most drug discovery organizations call the "hit to lead" stage. Some of these compounds may well be screening artifacts. Others will turn out to work through mechanisms that won't be useful - they'll kill malaria parasites, but they'll kill lots of other things, too. Some of them will hit other targets that aren't quite as severe, but will still be enough to make them undesirabel. And many others will be too weak to be useful as they are, and turn out, after investigation, to have no clear path forward to making them more potent. And so on.

The most interesting compounds still have a long road ahead. What are their blood levels after various sorts of dosing? Which of those dosage forms are the best - the most reliable, the easiest to make, the most stable on storage? What metabolites do the compounds form in vivo, and what do those do? What long-term toxic effects might they have? How susceptible are they to resistance on the part of the parasites? On top of all these questions are the big ones, about how well these potential drugs knock down malaria under real-world conditions.

This, in short, is what drug development is all about, and it would be good to see some of this brought out in the press coverage. This is what I (and many of the readers of this site) do for a living, and it's enough to occupy all our time with plenty left over. If you can do this sort of thing, you're a drug company, and I'm always looking for opportunities to tell people just what it is that drug companies do and to move people past the evil-pharma versus saintly-university mindset. Nature has it right in their editorial:

Meanwhile, universities and other academic institutions should do more to support and reward the sort of translational research required to develop drug leads such as those offered by GSK — even though that work usually does not result in high-profile, breakthrough research papers. In addition, such translational activities provide a means for universities to contribute to public–private partnerships such as the MMV, the Drugs for Neglected Diseases Initiative and the Institute for OneWorld Health.

Universities also have another part to play. Their often aggressive intellectual-property policies can stymie research and development in neglected diseases — they should ensure that their licensing deals with companies make exceptions for royalty-free use of technologies for good causes. That change, too, is beginning to happen — although, when it comes to hogging intellectual property, academics and their institutions are often among the worst offenders. . .

Comments (16) + TrackBacks (0) | Category: Academia (vs. Industry) | Infectious Diseases


COMMENTS

1. PharmaHeretic on February 2, 2010 9:39 AM writes...

Considering that drugs like quinacrine and chloroquine were developed at the very beginning of pharma's "golden age", the way forward involves iterative development using animal models of malaria.

Come to think of it, pharma's "golden age" ended when we stopped using relevant animal models at very early stages of drug development.

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2. J-bone on February 2, 2010 9:46 AM writes...

Forgive me if I sound naive, but I was under the impression that pharma companies don't pursue anti-malarials because there's no money in it, it's not a disease that affects wealthy countries with insurance companies that have deep pockets.

Funny story I heard about the Institute for One World Health, I was interviewing for a postdoc at an academic institution that had formerly had some collaboration with them and it turned out the the IOWH was only interested in stealing academic patents for themselves. Word got out to the Gates Foundation and the entirety of upper management was razed and replaced.

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3. Old Timer on February 2, 2010 10:11 AM writes...

If their existed a short, economical laboratory synthesis of artemisinin (or it's derivatives used in ACT), wouldn't the need for new antimalarials and expensive clinical trials be reduced dramatically?

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4. Jose on February 2, 2010 10:13 AM writes...

Sweet! So academic groups (already heavily handicapped by lack of experience, resources, and animal models) can now waste years sorting through piles of complete garbage combi-chem and HTS screening "hits" so GSK can fulfill its CSR mandate?!?! Hallelujah!

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5. Jose on February 2, 2010 10:17 AM writes...

Old Timer- sadly, there are already artemisinin resistant falciparum strains popping up in SE Asia- only a matter of time before it is as about as useful as chloroquine.

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6. anchor on February 2, 2010 10:50 AM writes...

When it pours it rains lot of irrelevant analogs. May be none of them are good, I guess!

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7. Sili on February 2, 2010 11:19 AM writes...

Any bets how long it will take before the woo-woos start selling the cheapest/most readily available hits from that screen as "THE DRUG THEY DIDN'T WANT YOU TO KNOW ABOUT!!eleventy-one"?

Derek, I wish you had a wider audience. Not that I have enough faith in the general public to expect them to listen.

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8. alig on February 2, 2010 11:20 AM writes...

GSK had (has?) a group in Spain devoted to developing drugs for neglected diseases (in particular, malaria). They have nominated a couple clinical candidates over the past decade, but ended up failing in GLP tox studies or early clinical trials.

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9. Hap on February 2, 2010 12:43 PM writes...

What is the point of universities doing the translational research from malaria lead to malaria drugs? It seems like developing malaria leads into drugs would be something better done by drug companies or governments (or by governments funding drug companies to develop with oversight) - groups that already have the appropriate experience, knowledge, and resources to do so. Unless the point of malaria drug development were to determine mechanisms of action, to generalize methods for lead optimization, ADME, etc. - to contribute some sort of general knowledge that everyone can use - you're just paying universities (or trying to get them to pay) to do things more effectively done by others, which seems like a waste of money and time.

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10. enzgrrl on February 2, 2010 1:07 PM writes...

Did I misread the press release, or is it really only the DATA and not the actual compounds that are being made available?

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11. Andy on February 2, 2010 4:18 PM writes...

Ok, so anyone has a clue where the structures/data are going to be deposited? I just tried to get hold of them but none of the press releases mentioned whether it will be in PubChem or some other place.

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12. Pharma Conduct Guy on February 2, 2010 7:08 PM writes...

Derek did a nice job of illuminating the important difference between a drug and a candidate. However, like Hap (#9), I'm wondering why the Nature comment says that universities should be taking pharma's leads and developing them. Finding good leads is the most uncertain and unpredictable part of the drug discovery/development process. Once big pharma has a good lead, they have an outstanding process for developing it, conducting clinical trials, dealing with the FDA, and conducting sales and marketing.

Although clinical trials are often run at university affiliated hospitals with the academics serving as PIs selected for their expertise in a particular disease area, they aren't the ones managing a single compound through the various stages. I don't know of any university that initiates its own trials after phase 1. Universities aren't set up to do those development side activities, nor should they be. As the Muno's paper pointed out, which we both discussed a few weeks ago, discovering an NME is a very stochastic, unpredictable process. Despite the massive amount pharma has spent trying to make this part of the process more predictable, whether discussing biologics or small molecules, even today, many of the best leads still have their origins in universities, coming from taxpayer funded NIH studies.

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13. cliffintokyo on February 2, 2010 7:29 PM writes...

@Nature:
"Universities....often aggressive intellectual-property policies can stymie R&D....when it comes to hogging intellectual property, academics and their institutions are often among the worst offenders. . ."

With good reason, when companies who they wish to collaborate with, produce contracts, drawn up by a team of lawyers, that tie the academics up in knots and leave them nothing, and no room to negotiate for the cost of a paper-clip - needless to say, US pharma are the usual culprits.


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14. researchfella on February 2, 2010 8:40 PM writes...

Good luck to those who want to follow up on those 13,500 "malaria compounds"... How do you prioritize compounds for the next studies, particularly when multiple different and unknown molecular targets were presumably hit by these compounds? Maybe I just don't know enough about anti-parasite R&D... Hopefully there is a distinct subset of 'drug-like' compounds with particularly striking potency.

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15. researchfella on February 2, 2010 8:47 PM writes...

@Pharma Conduct Guy:
"Finding good leads is the most uncertain and unpredictable part of the drug discovery/development process."

Yes, and these 13,500 compounds aren't "leads", they're just screening hits. The next step, to develop some good leads out of this heap, is indeed a very challenging and uncertain process.

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16. Teodesian on February 3, 2010 6:04 PM writes...

I find it difficult to see efforts like this, when announced, as being particularly good press to the party engaging in them. If these are indeed useful hits, then they are not good businessmen for passing them up. However, if nothing comes of these (despite thorough investigation) a case could be made for this being a waste-trap for their competitors (thus making them active malefactors). Of course both outcomes would still leave the true intent behind this impossible to prove.

Either way, the real heroes here will be the ones that will be using this data, regardless of it's nature or usefulness.

What really endears pharmas to the people is creating useful products and selling them (rather than the things like merger-mania and financial shenanigans that get most of the headlines). Sadly, the really useful stuff is few and far between (nature of the biz) -- while the stock price changes every day. So I suppose we can expect the press to continue to paint pharma as a boogeyman.

There is usefulness for GSK in this however. It certainly gives prospective employees warm feelings toward them (the audience of this blog). Maybe they can translate that into lower employee costs in the future...maybe.

As for the usefulness to humanity, we'll just have to wait and see.

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