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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 10, 2013

Pharmacology Versus Biology

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Posted by Derek

There's a comment made by CellBio to the recent post on phenotypic screening that I wanted to highlight I think it's an important point:

In drug discovery, we need fewer biologists dedicated to their biology, and more pharmacologists dedicated to testing the value of compounds.

He's not the first one to bemoan the decline of classic pharmacology. What we're talking about are the different answers to the (apparently) simple question, "What does this compound do?" The answer you're most likely to hear is something like "It's a such-and-such nanomolar Whateverase IV inhibitor". But the question could also be answered by saying what the compound does in cells, or in whole animals. It rarely is, though. We're so wedded to mechanisms and targets that we organize our thinking that way, and not always to our benefit.

In the case of the compound above, its cell activity may well be a consequence of its activity against Whateverase IV. If you have some idea of that protein's place in cellular processes, you might be fairly confident. But you can't really be sure about it. Do you have enzyme assays counterscreening against Whateverases I through V? How about the other enzymes with similar active sites? What, exactly, do all those things do in the cell if you are hitting them? Most of the time - all of the time, to be honest - we don't know the answers in enough detail.

So when people ask "What's this compound do?", what they really asking, most of the time, is "What does it do against the target that it was made for?" A better question would be "What does it do against everything it's been tested against?" But the most relevant questions for drug discovery are "What does it do to cells - and to animals? Or to humans?"

Update: Wavefunction, in the comments, mentions this famous article on the subject, which I was thinking of in the first paragraph after the quote above, but couldn't put my finger on. Thanks!

Comments (16) + TrackBacks (0) | Category: Drug Assays


COMMENTS

1. Curious Wavefunction on April 10, 2013 10:12 AM writes...

I am always reminded of a fantastic editorial that Gerry Higgs wrote in Drug Discovery Today (Sep 17, 2004 issue) where he bemoaned the focus on reductionist molecular biology and the neglect of classical pharmacology techniques (Higgs also reminds us that some of the most successful drugs are remarkably non-selective). Elion and Black both discovered blockbuster drugs using good old pharmacology.

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2. Kevin Gaffney on April 10, 2013 10:37 AM writes...

@ Curious W. To save time, here is link to Gerry Higgs' article http://www.sciencedirect.com/science/article/pii/S1359644604031435

It is unfortunately behind a pay wall.

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3. Cellbio on April 10, 2013 11:10 AM writes...

Made my day! Thanks Derek, it is an honor be part of the community you have formed.

Regarding "what does this compound do?", my work history provided a great perspective that informed my approach. I was a mol bio person placed into a Pharmacology dept that handled all things preclinical, models, PK, tox and formulation work. In that setting, I noticed the Whateverase IV inhibitors would be tested only for endpoints in models, often with an aggregate score referred to as a clinical score. I wondered about the other stuff, like demonstration of Whateverase inhibition after dosing, Otherase inhibition, and began to measure, and show, that way too often achieving endpoints consistent with target inhibition occurred without target inhibition. This led to creating a battery of cell biology endpoints (cytokine production, proliferation, activation marker upregulation) with mechanistic reads (phosphorylation etc). In turn, this showed disconnects in some med chem programs and greater complexity in all programs and in turn the conclusion that, as you say, we had to empirically determine what the compound did to cells, animals and humans.

If we could figure out how to do the first part much better, we could reduce the frequency of spectacular and expensive failures when we find out what the compound does to humans, and before that, curtail costs and wasted effort in scale up of 'poisons" for pharmacology and toxicology. This worked well and led to our pathway screen, the logic being that since the empirical approach was the final determinant of success why not start with that in addition to target based efforts.

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4. MDA Student on April 10, 2013 11:17 AM writes...

As a Cancer Biologist I can't help but agree.
To stereotype it seems as though:
1.Every biologist has their trophy protein/mechanism.
2.Every pharmacologist indiscriminately throws a mass (or in some cases a class) of compounds at an assay.

You can get pretty far (maybe by luck?) with guy #2. Guy #1 is going to fail more often but when he does you tend to have a better idea of why.

As a grad student [I think] I figured a way to address this, but funding is funding is funding, and we had our favorite protein to work on.

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5. luysii on April 10, 2013 11:18 AM writes...

Unfortunately, this was also true in clinical medicine when I was in practice.

Aspirin is a great drug, and it had been shown that taking it decreased the stroke rate in those at risk. Back in the 80s and 90s once its effect on cyclo-oxygenase (COX) was known, people measured how much was enough to inhibit COX, to establish the dose.

The assumption behind this, was that COX inhibition was how aspirin produced its benefits. I thought this unlikely, and chose the dose producing the greatest reduction in stroke incidence in all the studies I could find. It turned out to be quite high (2 adult aspirins twice a day -- total 1300 milligrams). The cardiologists used much lower doses to prevent heart attack (baby aspirin around 80 mgms), and as was typical of them (as compared to neurologists) they had actual data to back this up (data -- what a concept ! ! and one unknown to neurology at the time, theoreticians par excellence).

However, anyone who's ever dissected a cadaver knows that coronary arteries look quite different from brain arteries. The former have to be tough and muscular (they're attached to something moving all the time), the latter are quite thin and delicate -- you can sometimes even see through the basilar artery (one of the the largest arteries inside the head) at post.

So I took to making a list of the non-cyclo-oxygenase actions of aspirin, to convince colleagues that I was doing the right thing (this was long before the generality of protein acetylation of aspirin was known).

Here are a few -- reaction in the activity of coagulation factors II, VII, Xi X in a dose dependent manner --increased fibrinolytic activity of whole blood -- inhibition of NFkappaB activation -- inhibition of nitric oxide synthesis -- promotion of the synthesis of 15 epi lipoxin. I'm sure there are more now -- particularly its effects on histone acetylation.

Referring docs knew I loved theory, and some of them let me use the higher dose (remember neurologists are consultants to other docs for the most part). At the time I retired in 2000 there had never been a head to head study of the various doses of aspirin in stroke prevention. Historical controls are no good, due to the gradual improvement in medical management of hypertension, hyperlipidemia, diabetes, etc. etc.

It's exactly the same thing Derek was talking about in his post. Unlike Derek's effects which are preclinical, this sort of thing may have had dramatic effects on people's lives (not that Derek's concerns won't eventually).

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6. Anon on April 10, 2013 12:33 PM writes...

luysii, you may be interested the aspirin resistance paper published a couple of months ago.
http://www.ncbi.nlm.nih.gov/pubmed/23212718

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7. processchemist on April 10, 2013 1:27 PM writes...

About classic unexpected events: recently a customer told us that they developed nanomolar inhibitors of a whateverase -popular target in oncology (structural modifications of a well known class of compounds)- but...
the best lead, on the results of the xenographt tests, turned out to work by a still unknown and different mechanism not involving whateverase... but maybe you can find the compound from some authorized vendors with the label "nanomolar whateverase inhibitor".

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8. luysii on April 10, 2013 1:54 PM writes...

#6 Anon: -- Interesting paper and thanks but the paper still contains the implicit assumption that aspirin is producing its effects by cyclo-oxygenase inhibition. Can anyone out there tell me if aspirin acetylates histones, given the current interest in histone deacetylase inhibitors (HDACi's) as antineoplastic drugs?

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9. Curious Wavefunction on April 10, 2013 2:39 PM writes...

luysii: There's at least a few papers indicating acetylation of multiple proteins by aspirin and questioning whether it affects post-translational modification. Research on the effects of aspirin on proteins like nitric oxide synthase goes back at least two decades.

It would not surprise me at all to know that aspirin hits multiple targets. Some of the best known drugs are non-selective and aspirin is a particularly reactive and simple small molecule. You might also be interested to know that the IC50 of aspirin for COX-2 is embarrassingly high, almost 20 millimolar.

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10. Oldnuke on April 10, 2013 3:10 PM writes...

> "It's a such-and-such nanomolar Whateverase IV inhibitor"

Followed by the organic chemist's lament:

"Made of Practically UnObtainium 42"

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11. PharmaHeretic on April 10, 2013 3:56 PM writes...

Any comments? LOL

"GlaxoSmithKline's ($GSK) top scientists have staked out a pioneering role in an incipient field in the drug discovery world, rolling out a slate of new initiatives designed to sound the starting gun in a long-running effort to develop new therapeutics that can fight disease by targeting the electrical signals that harmonize human biology."

--
GlaxoSmithKline stakes a pioneering effort to launch 'electroceutical' R&D

http://www.fiercebiotech.com/story/glaxosmithkline-stakes-pioneering-effort-launch-electroceutical-rd/2013-04-10

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12. Arm on April 10, 2013 8:53 PM writes...

The leg is such a pain in the a$$. But we are stuck with each other.

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13. simpl on April 11, 2013 6:31 AM writes...

The same dichotomy occurs at the marketing end. A nice pharmacology whateverase-IV theory helps to sell to early-adapting doctors. The cautious ones hold back, waiting for medical opinion to pronounce that it helps when treating arthritis, headache, etc. We've seen enough drugs that launch well, then bomb because of this.
It is not just a Pharma thing, either - top speed or acceleration of a car are sales arguments, and being useable when driving round my patch is the reality check.

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14. marcello on April 11, 2013 8:55 AM writes...

I started out my drug discovery adventures with the idea "the more compact the molecule the better" but over the years I have been constantly reminded of the fact that small molecules because of their size, penetration and relative promiscuity will always find some targets to hit we don't know about, whether for good or for bad.
That's why phenotypic drug discovery was relatively succesful and that's why biologics and their "clinical hit-rate" are on the rise.
Macromolecules are by definition and their characteristics much more specific. the big question is how to deliver them in some places...

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15. Anonymous BMS Researcher on April 11, 2013 9:04 PM writes...

My wife says Whateverase IV inhibitors involve coordination chemistry of the Meh-5 ion.

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16. Jack Scannell on April 14, 2013 1:14 AM writes...

"What does this molecule do?" is a special case of the general problem of relating structure (e.g. drug, gene product, "target") to function in biology.

Years ago, a couple of colleagues (Malcolm Young, Claus Hilgetag) and I became interested in some of the problems that neuroscientists had in trying to relate structure to function. Both Malcolm Young and I are now interested in drug discovery. We recently dug out an old neuroscience paper we wrote, and were surprised how relevant it appears to drug R&D.

We wrote of neuroscience: "'function' appears to be applied in at least the following different senses: the evolutionary biological sense, of function as a survival function, Fc; function as a discrete local property, Fl; function in the context of the network, Fc; function in the sense of the function of the global nervous system, as in its behaviour, Fg; and function in the formal sense of a mathematical mapping between input and output, Fm..."

In the article, we went on to discuss the problems that arise when trying to map between the different senses of "function". The general arguments bear on things like the difference between a drug's whole-animal phenotypic effects (Fg, above) and a drug's molecular "targets" (Fl, above). In many, probably most, cases, one should not expect a simple mapping between Fg and Fl. This tends to reinforce the idea that we need more whole-system pharmacology and less molecular reductionism.

If you suffer from insomnia, the gritty details, are available in: Young, Hilgetag, & Scannell (2000) Phil. trans. Roy. Soc. B 355(1393), pp147-161.

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