About this Author
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: Twitter: Dereklowe

Chemistry and Drug Data: Drugbank
Chempedia Lab
Synthetic Pages
Organic Chemistry Portal
Not Voodoo

Chemistry and Pharma Blogs:
Org Prep Daily
The Haystack
A New Merck, Reviewed
Liberal Arts Chemistry
Electron Pusher
All Things Metathesis
C&E News Blogs
Chemiotics II
Chemical Space
Noel O'Blog
In Vivo Blog
Terra Sigilatta
BBSRC/Douglas Kell
Realizations in Biostatistics
ChemSpider Blog
Organic Chem - Education & Industry
Pharma Strategy Blog
No Name No Slogan
Practical Fragments
The Curious Wavefunction
Natural Product Man
Fragment Literature
Chemistry World Blog
Synthetic Nature
Chemistry Blog
Synthesizing Ideas
Eye on FDA
Chemical Forums
Symyx Blog
Sceptical Chymist
Lamentations on Chemistry
Computational Organic Chemistry
Mining Drugs
Henry Rzepa

Science Blogs and News:
Bad Science
The Loom
Uncertain Principles
Fierce Biotech
Blogs for Industry
Omics! Omics!
Young Female Scientist
Notional Slurry
Nobel Intent
SciTech Daily
Science Blog
Gene Expression (I)
Gene Expression (II)
Adventures in Ethics and Science
Transterrestrial Musings
Slashdot Science
Cosmic Variance
Biology News Net

Medical Blogs
DB's Medical Rants
Science-Based Medicine
Respectful Insolence
Diabetes Mine

Economics and Business
Marginal Revolution
The Volokh Conspiracy
Knowledge Problem

Politics / Current Events
Virginia Postrel
Belmont Club
Mickey Kaus

Belles Lettres
Uncouth Reflections
Arts and Letters Daily
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

« Reality, Here In This Little Dish | Main | An Innocent Question »

January 10, 2007

Upside Down Activity

Email This Entry

Posted by Derek

After yesterday's post, several people brought up the issue of inverted screening cascades. What happens when your compound works better in the mice than it did in the cells? Worse, what if it would have worked in the mice, but you never put it in there because it was so weak in the cell assays?

These kinds of questions are worth worrying about, because we almost never get a chance to answer them. For obvious reasons, the vast majority of compounds that make it into animal models are ones that looked good in the earlier steps. You'd have to think that the hit rate in vivo would be much lower for the dud compounds, but you'd have to be pretty arrogant to think that it would be zero, too.

As I recall (and I was just down the hall when it happened), the discovery of Schering-Plough's cholesterol absorption inhibitor came out of a compound that made it into an animal model and worked well, even though it turned out later to be a loser at the project's original target. (I believe that the in vitro assay was down that week for some reason, but one of my former colleagues will probably set me straight if I'm wrong about that). This sort of thing is food for thought, all right, extreme example though it might be. Even if your compounds don't suddenly hit a new target, there's still room for plenty of surprises in pharmacokinetics and the like.

But it would be unethical just to shove everything into animals, tempting though it is sometimes. And it would cost an insane amount, too - let's not forget that. But I do advocate getting as close to the real disease as quickly as possible. You can really waste time and effort by over-optimizing in vitro, all the time convincing yourself that you're doing the right thing.

Then there's the ultimate question in this line: how many compounds are there that don't work well in the animal models, but would be good in humans? I've wondered about this for many years, and I'm going to go on wondering, because data points are mighty scarce. Human biomarkers might eventually lead to some companies crossing their fingers and going into man with a compound that they expect to outdo the animal models. But it's going to take a lot of nerve. (And here's another complication - those upside surprises that might show up in the animals? How many of those are going to translate to humans, do you think? Not all of them, clearly. . .)

I have no doubt that there are many potentially useful drugs that are abandoned early. False negatives are probably on the shelves all around us. I don't see that as a strong argument against animal use (what, after all, is the alternative?), but it sure isn't a big argument for it, either. It's just, for now, the way things are.

Comments (11) + TrackBacks (0) | Category: Clinical Trials | Drug Assays | Drug Development


1. milkshake on January 11, 2007 12:59 AM writes...

Fluconasole is an unimpressive inhibitor in vitro but has excellent PK. The group at Pfizer that discovered Fluconazole tested all their compounds in animals against Candida invasion - they actualy used those animals as a primary screen. (They also optimized their molecules for metabolic stability while keeping them small and not too greasy.)

Other industry groups missed this opportunity - Fluconasole structure comparison with Ketoconazole or Itraconazole is an example of good versus bad molecule design.

Permalink to Comment

2. Milo on January 11, 2007 7:01 AM writes...

Well, if AMS becomes readily accessible to the masses (I don't know that status of this technique), you could at least look at PK via micro dosing in your favorite species a lot earlier.

Permalink to Comment

3. waiting4data on January 11, 2007 11:04 AM writes...


Your discussion about the use of in vivo models as a primary screen is very interesting, as it was the topic of conversation at my lunch table yesterday. There are a number of recent BMCL papers by scientists at J&J discussing the discovery of several new SARM scaffolds (selective androgen receptor modulators), the most recent being in the current issue (vol 17, issue 2). No in vitro data is presented in these papers -- not even for the lead structure -- and they discuss developing SAR using the in vivo assay, citing "fast turnaround time, reasonable compound amount (~40 mg for each test), and simplified data analysis" as the benefits of this approach. An analysis, by us, of this approach generated many questions, especially since there was no exposure data cited to normalize the observed in vivo activity. Is this really SAR?

Permalink to Comment

4. GATC on January 11, 2007 11:18 AM writes...

Yes, this is all too common with in vitro HTS-based assays for antimicrobial discovery. One can get some very nice hits in a purified enzyme assay, but then little or no potency in whole cell profiling assays. A real bummer indeed.

It is interesting to reflect back on the very first antibacterial; prontosil. This insoluble dye was practically inactive against bacteria in vitro, but in vivo, the molecule is subject to azo-reduction yielding sulfanilimide, the first sulfa drug. Imagine how far behind we would be if the Bayer scientists had only gone with the in vitro results. Some would argue that the outcome of WWII may even have been different or at least delayed a bit until penicillin was more readily available.

Permalink to Comment

5. BlogReader on January 11, 2007 1:21 PM writes...

"The Demon Under the Microscope" had a bit about one 'sulfa' drug didn't work in a test tube but did in a mouse, I believe it was done in a mouse by accident. Why do experiments not work in vitro but in vivo? Is it because all the feedback loops haven't been included in the test tube?
If upon seeing this discrepancy do you go back and see what else should be included in your scaled down experiment? How do you know what to include that wasn't in there before? Do you look at the mouse output and notice that protein XYZ shows up in great amounts and so you might have to include that in your test tube?
As you can tell I know nothing about this field, and am but a lowly computer programmer that likes this blog.

Permalink to Comment

6. Eric J Johnson on January 11, 2007 5:49 PM writes...

That one sulfa drug you read about was probably none other than prontosil itself, the first sulfa drug, and first reasonably nontoxic antibacterial.

In this case, I believe the drug (itself inactive) is catabolized by the mammalian body into two fragments, one of which is active. This particular catabolism is not carried out by microbes, so prontosil is inactive on pure microbial specimins.

Domagk, one of the workers developing prontosil, experimented on his daughter (who had a life-threatening infection) and the rest is history.

I think someone figured out fairly quickly what was going on with the catabolic activation of the drug, but I don't know how.

Quite a few infections are poorly responsive to sulfa drugs, or(?) at least to the old sulfa drugs, so it was still very impactful when penicillin was developed several years later. Apparantly Alexander Fleming was unable to interest anyone in his now-famous serendipitous observation of antagonism between bacteria and molds (which is also supposed to have been observed by others as well)... and penicillin was not developed until many years afterward. The Allies realized penicillin could get syphilitic etc soldiers back into combat, and pounced on that idea. In 1943 or '44 or so, the UK and US had, I think, dozens of labs working furiously on the problems of scaling up penicillin production. By the time the war ended they were making enough to treat lots of people.

Permalink to Comment

7. Bootsy on January 13, 2007 12:25 PM writes...

I case people here don't know about it, Chris Lipinski (of Rule of 5 fame) has been running around talking abour Melior. This compnay runs failed late-stage compounds through a whole battery of in vivo models looking for previously undiscovered effects.

The premise is that these are compounds with good PK that failed in whatever animal model they were being used in, but stand some chance of being active on other targets. Alternatively, they may hit their desired target and it was a bad target for the disease it was meant for, but a good target for some other indication. Apparently, the latter is more common.

He claims a pretty high success rate for this.

Permalink to Comment

8. Kay on January 14, 2007 8:54 AM writes...

Lipinski has cost this industry incalculable sums of sorrow and money. Step carefully.

Permalink to Comment

9. milkshake on January 14, 2007 7:25 PM writes...

Lipinsky popularized common-sense drug design tendencies. His scoring explains to some degree why would a medicinal chemists instinctively call some molecule a nice or an ugly structure. It is not Lipinski's fault that stupid people did stupid things with his shorthand.

When I was at Celera some management folks there had this "funnel" of stringent rules that each new analog had to satify before even being considered for PK. (Caco-2, microsomal strability, polar surface area, and of course Lipinski score). It was all arbitrary stuff but it gave them the air of profundity, to these pompous people that never saw a late-stage drug development before - and I did not make myself very popular on the meetings there by bringing up examples of successful drug that would fail their criteria.

Permalink to Comment

10. Bootsy on January 15, 2007 7:00 PM writes...


I am sorry if I gave the impression that I am a big Rule of 5 supporter. Actually, like Milkshake, I prefer to point out the exceptions and I don't think he's to blame for the fact that people wanted to make a Rule out of his retrospective analysis.

Rather, let us say that overapplication of simplistic rules to complex problems without performing the experiment has cost the industry.

I do think the Melior approach is interesting, in a very "back to the future" way.

Permalink to Comment

11. Kay on January 16, 2007 5:10 PM writes...

"Rather, let us say that overapplication of simplistic rules to complex problems without performing the experiment has cost the industry."

Very well put!

Permalink to Comment


Remember Me?


Email this entry to:

Your email address:

Message (optional):

The Last Post
The GSK Layoffs Continue, By Proxy
The Move is Nigh
Another Alzheimer's IPO
Cutbacks at C&E News
Sanofi Pays to Get Back Into Oncology
An Irresponsible Statement About Curing Cancer
Oliver Sacks on Turning Back to Chemistry