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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 16, 2012

Phenotypic Screening's Comeback

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Posted by Derek

Here's an excellent overview of phenotypic screening at SciBx. For those outside the field, phenotypic screening is the way things used to be all the time in the drug discovery business, decades ago: (1) give compounds to a living system, and watch what happens. (2) Wait until you find a compound that does what you want, and develop that one if you can.

That's as opposed to target-based drug discovery, which began taking over in the 1970s or so, and has grown ever since as molecular biology advanced. That's where you figure out enough about a biochemical pathway to know what enzyme/receptor/etc. you should try to inhibit, and you screen against that one alone to find your leads. That has worked out very well in some cases, but not as often as people would have imagined back at the beginning.

In fact, I (and a number of other people) have been wondering if the whole molecular-biology target-based approach has been something of a dead end. A recent analysis suggested that phenotypic screens have been substantially more productive in generating first-in-class drugs, and an overemphasis on individual targets has been been suggested as a reason for the lack of productivity in drug discovery.

As that new article makes clear, though, in most cases of modern phenotypic screening, people are going back from their hit compounds and finding out how they work, when possible. That's actually an excellent platform for discoveries in biology, too, as well as for finding medicinally active compounds. I'm glad to see cell- and tissue-based assays making a comeback, and I hope that they can bail us all out a bit.

Comments (30) + TrackBacks (0) | Category: Drug Assays | Drug Industry History


COMMENTS

1. David Borhani on April 16, 2012 9:24 AM writes...

Interesting post, Derek. One might argue that target identification is still being overemphasized. Mark Fishman notes that “What becomes slower is discovery of the target and target validation,” to better enable validation and structure-based design; and SciBX attributes to Mike Varney the concept that knowing the target is critical because the company's pipeline portfolio committee would always favor advancing a compound with a known target into development.

These concepts make most sense in a "rational" world. Sure, it's fun to use all these modern tools. In an "irrational" (read: pharmacologically driven) world, however, they make sense only if they add value (cf. eroom's law).

I think we need to put ourselves back into a 1950s-1960s mindset: Drug candidate A has great in vivo efficacy and a great therapeutic index...but we have no idea of the target. Candidate B is inferior in every regard...but we know its target. Should we develop A or B? Most of us (me included) would pick A, for many good reasons.

*Finding* candidate A is the issue. But, if the screens have been crafted carefully, and can thus be trusted to weed out the junk (think: we used to have a much tighter link between pharmacologists and medicinal chemists), then the value of target identification is, I believe, significantly lowered.

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2. Anonymous on April 16, 2012 9:37 AM writes...

I second this.

My belief is that target based approaches have generally failed because we have massively overestimated how much we understand about the disease and what we need to do/how to fix the problem at the time of target selection. Most hypotheses proposed actually have hardly any human patient data underlying them and a huge amount of assumptions baked in when the are finally dissected (usually after a POC failure). The sequencing of the human genome has actually made all this worse as is became very easy to put hypotheses together with little or no human disease biochemistry/ physiology to back it up!

Phenotypic screens start with the simpler 'we don't know what is going on at the molecular level but we have a physiologic endpoint we truly believe' mindset. It is not easy (how could it be!) and you still need to be careful of the assumptions you have with these models (like all models, if these are wrong it will not predict success) but if you have less assumptions you will carry less risk forward and are more likely to be successful.

Over the last 20 years we have spent a fortune on improving med chem, PKPD, safety etc and we are seeing better compounds than ever move forward. However, we are paying the price in all the current job losses for not fixing the biology piece. If you pick the wrong target at the beginning all your subsequent effort is wasted - the approach won't work - ever. 'Shots on goal' is a flawed strategy as there are too many opportunites to 'miss the goal' as we have collectively as an industry proved.

We need to become a little more humble concerning how much we actually 'know' about human disease at the molecular level and build strategies accepting this (unwelcome) starting point, relearning how things were done in the 50-90's to discover new targets and building upon them. Phenotypic screens can play a part in this and help 'bail us out'.

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3. HTSguy on April 16, 2012 10:38 AM writes...

While I agree that phenotypic screens can play an important role, they also do not provide the information you really want to know - "how will this compound perform in diseased humans?". The same lack of knowledge that prevents us from efficiently using target-based screening prevents us from constructing predictive cellular, tissue, or animal models. How many times have animal models with "face-value", but little mechanistic understanding, led us down the wrong path (think neurokinin receptors for pain, as just one example).

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4. Wile E. Coyote, Genius on April 16, 2012 10:49 AM writes...

Phenotypic is one solution but not the answer. So many on this blog have lamented the poor predictability of efficacy in a cell-based or animal model that don't translate into clinical trial effects. How do you phenotypically identify efficacious drugs for many of the disease indications being pursued these days? Psychiatric disorders are good examples of diseases that are very hard to model in animals or cells. If you think you know the target, then it become easier to discover a drug candidate. A robust phenotypic model, if available, is what is needed to make a phenotypic approach work. So often these are absent.

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5. Maks on April 16, 2012 10:50 AM writes...

@HTSguy: Do you have a good review article on the neurokinin receptor story? Have to admit never heard of it in that context. Thanks!

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6. road on April 16, 2012 10:59 AM writes...

but how is it possible to screen many compounds in mice? I can see how you could run a few hundred compounds through a disease model this way... but thousands? tens of thousands? It seems to me like you must have a lead molecule or class of compounds to do something like this...

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7. imatter on April 16, 2012 11:00 AM writes...

I made a phenotypic screen with my agent if only because "cell survival or proliferation assays" were not telling me the whole story. I learned that phenotypic screen can give a good mechanistic related response (I can see what the agent is doing). And it was specific!

It's a good starting point--ultimately the pharmacology (doses and kinetics) will have to determine its utility.

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8. HTSguy on April 16, 2012 11:08 AM writes...

@Maks: Here is a review by Ray Hill, who lead the program at Merck:

http://dx.doi.org/10.1016/S0165-6147(00)01502-9

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9. Biotechtranslated on April 16, 2012 11:11 AM writes...

The biggest difference between target-based and phenotypic screening is the approach to discovery.

Target-based screening = find a target that should have a therapeutic effect and translate that to the larger model (living organism)

Phenotypic screening = look for the therapeutic effect, then find out why it works (however, why it works is not required knowledge)

It's not as if one is ALWAYS better than the other, it's just that they are very different approaches.

It would seem as thought target-based screening is most appropriate for optimization (you know what it should be doing so you make it do it better) vs. phenotypic screening which seems more appropriate for the discovery of unknown therapeutic pathways.

Since biopharma seems to be lacking more in the second area than the first, it seems like the shift towards phenotypic screening is a positive move.

Mike

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10. Anonymous on April 16, 2012 12:21 PM writes...

Having been involved with many phenotypic screens in industry (screening compound libraries against various in vitro cell culture systems), I declare myself a skeptic of the approach. Too frequently, the readouts fail to distinguish biologically-desired effects from stress responses induced by toxic compounds. All we ever found where compounds that modulate targets already connected to the phenotypic response. It is asking a great deal to detect via a cell-based system a novel pharmacology for the disease (think low affinity interaction with the 'new' target) with libraries of molecules made for cell surface receptors, etc. The Swinney / Anthony review makes good reading on the promise of phenotypic screens, but when one excludes antifungals / antibiotics, the number of compounds discovered via animal models is ~2x that discovered via in vitro cell-based screens.

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11. Anonymous on April 16, 2012 2:04 PM writes...

Are the phenotypic screens different to the animal models that currently don't seem to be doing much good either?

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12. Maks on April 16, 2012 4:45 PM writes...

@HTSguy: Many thanks for the quick response and the interesting review!

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13. Clueless on April 16, 2012 5:41 PM writes...

The dust will settle somewhere in between if you know what I mean........

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14. biotechbaumer on April 16, 2012 7:03 PM writes...

Aren't we talking about two sides of the same coin? Whether you identify your hits by target-based or phenotypic screens, you are going to want to validate your compounds with the other approach. If I find a molecule that hits my target, I am going to need to have a cellular assay (ie. phenotypic readout) to make sure my compound has cellular activity, and is doing what I want it to do (eg. affect viability). Both approaches are inherently intertwined, no?

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15. biotechbaumer on April 16, 2012 7:15 PM writes...

Just to clarify...phenotypic HTS obviously has its benefits over target-based in that you're not limiting yourself to one target; however, the notion that a phenotype-based screen might yield more drugs than the target-based approach because you're screening against a phenotype, doesn't make sense to me. In the target-based strategy, you will validate your compound with a phenotypic assay (likely the same one you would have used for a phenotypic HTS!)

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16. daen on April 16, 2012 8:52 PM writes...

I may be being naive here but I can imagine a not-too-distant future where a combination of target and phenotypic screens might work in tandem. Given the current downward plunge of sequencing costs, it becomes increasingly feasible to repeatedly sequence a cell line's cDNA, both for baseline and in response to a number of compounds, which would show what's going on at the molecular level for those compounds which show, for example, apoptotic behaviour in cancer lines.

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17. Rick Wobbe on April 16, 2012 9:01 PM writes...

For this discussion to ever make significant progress, we need to disabuse ourselves of several popular delusions:

The first is that there is, ever was or ever will be a "drug discovery process". You know, the diagram that starts with "Target Discovery" on the left, proceeds through a set of linear arrows with labels like "Target Validation", "HTS", "Preclinical", and ends with "marketed drug" on the right that you see on the FDA, BIO and PhRMA web sites and countless articles and presentations. Forget about selecting a "winner" between so-called phenotypic and target-based screening! The most significant, fundamental take-home message from the papers Derek cites (Jack Scannell et al) is that there is NO one right scheme to go from unmet medical need to marketed drug and that trying to force fit all programs to a "Drug Discovery Process" of any sort was our big mistake.

The second popular delusion is that you need to know the target to discover a drug, or the related statement, uttered in too many pharma conference rooms, that you simply can't develop a drug if you don't know its target. I hope every reader of this blog is familiar enough with the history of this industry to know there are many, many examples of breakthrough drugs that reached market and did amazingly well both financially and medically without knowing the target. That doesn't mean that finding out the target and/or using target-based screens are useless. It can be used to discover drugs in the first instance, it helps advance programs through tricky SAR-related optimization challenges and in some cases there simply is no good phenotypic screen (Alzheimer's comes to mind with all due respect to the genetically engineered animal efforts). But the blanket statement that "knowing" the target is sine qua non for any program to advance appears to have been sheer folly that has prematurely killed more programs in their cradles than we will ever know.

The third popular delusion is that there are "experts" at drug discovery who can offer the right prescription for any new program, regardless of whether it is related to their past experience. I've been lucky enough to know a few of the great people who have pioneered multiple new therapeutics who have become regarded as experts in this sense and one thing that's struck me most about them is the respect and humility with which they approach every new project. The most common advice I've heard is that every new discovery program has unique challenges that no other program ever faced and that while their advice may help, by and large "you're on your own, buddy, so put on your own thinking cap". I'm not trying to be a nihilist here, but it is important to understand that expert advice is but one tool that can't substitute for the agile mind that is prepared to take advantage of times when reality veers off the trodden path as well as use sound advice and existing tools when warranted.

What this boils down to is that arguments over whether phenotypic screening is better than target based screening or some specific mix is best are silly unless and until you're talking about a specific discovery program. Then, at the extremes you may have to depend only on biochemical target assays if the first available phenotypic screen is a clinical trial (that's happened!) or you may find that you don't need a target or a target based screen to optimize a drug candidate that does well in the clinic (that's happened too!) or you may find that knowing the target becomes crucial to get past the infamous micromolar potency barrier. If the papers Derek cited are used to justify a swing toward phenotypic screening uber alles that is equal and opposite to the target uber alles mindset that characterized the past 30 years, as if the new tools discovered during that time have nothing to offer, we can look forward to more decades of disappointment.

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18. Rick Wobbe on April 17, 2012 9:55 AM writes...

There may be value in debating some of the statements from the SciBX article because they seem to reflect broadly accepted notions that may not be accurate and/or useful.

1. "...preclinical and clinical development is substantially more challenging with an unknown target, particularly because it is more difficult to predict mechanism-based toxicities." How often does mechanism of toxicity of a drug have anything to do with its mechanism of action? If the answer is "rarely", which I believe is the case, then this seems like a weak rationale for holding up a program that is making great progress.

2. "A commitment to phenotypic screening requires complementary methods to subsequently identify the targets of active molecules." Why, exactly, is it required? Knowing the target can help solve specific SAR or optimization challenges, but how often is that necessarily true and how can you know in advance? Universally applying this "requirement" from the get-go may pointlessly "jest at scars that never felt a wound".

3. "…too much time and resources are needed to identify the targets of a phenotypic screen." Too much relative to what? Relative to the time and resources wasted on targets that prove non-druggable or irrelevant to the disease? Relative to the budget of the manager or funding source? Let's not overlook the fact that clinical trials are the biggest, most expensive "phenotypic screen" there is; any phenotypic screen preceding clinical trials is a bargain by comparison. In this context, the statement "even with the greatest phenotypic readout the project won't compete in the portfolio,” seems a bit narrow-minded for the broader drug discovery enterprise.

4. "knowledge of the target is not always a regulatory requirement for drug approval." Indeed, exactly how often is it a regulatory requirement? One way to ascertain that is to look through FDA guidance statements. In my experience, although a mechanism is occasionally "nice to know", it is rarely a stated requirement.

5. “We had nice chemical leads and they looked good in our phenotypic assays, but all lost out on prioritization to target-based screens because we couldn't tell someone what the target of the molecule was.” If “looking good” means that the potency, SAR, DMPK and toxicity profiles, which are the key criteria for prioritization, are advancing, then maybe we need to ask “someone” the pharmacological reason for holding back a project. This is most needed in cases where phenotypic leads have been deprioritized vis a vis target-based leads even thought the latter have, for example, mediocre potency, poor absorption and unexplained toxicity.

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19. C-Me on April 17, 2012 11:13 AM writes...

Rick Wobbe: True, all of that. Thanks for the eloquent dose of reality.

**Free Screening** For any academics or small biotechs out there that are interested in getting some phenotypic screening done for free, Lilly has a program called Open Innovation Drug Discovery. Several screens, including a global disease target (tuberculosis). It is totally blinded and you can take the data and run, no strings attached (unless you want to move with Lilly on a good hit). You sign up, send structures (sd files) to a secure 3rd party that makes sure they are not in the Lilly collection and are not nasty compounds. Then they will invite you to send actual compound to Lilly. They will not know the structure. They send you the data and you can walk away. Publish or take it on. If they like the data they will invite you to enter a collaboration, but you are under no obligation. I am not a Lilly employee nor fan, but this program seems legit.
C-Me

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20. chris on April 17, 2012 2:19 PM writes...

For a similar view, think of artemisinin and the search for newer anti-malarials

http://arstechnica.com/science/news/2012/04/after-artemisinin-prospects-for-new-malaria-drugs.ars

chris

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21. Jimbo on April 18, 2012 8:22 AM writes...

I dont disagree with the value of pheno screening but let's not forget the major successes like Gleevec, Velcade, the new BTK inhibitors which are having great recent clinical success, herceptin etc etc.

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22. Rick Wobbe on April 18, 2012 8:50 AM writes...

C-Me #19, Thanks for sharing the info about the Open Innovation Drug Discovery program. Sounds like fodder for the (hopefully ongoing) Mrs. McGreevey discussion.

The only true thing in my diatribes is that we should question truthiness. There's much of truthiness in the SciBX article.

Jimbo, #21. Agree whole-heartedly, as long as we don't lose sight of the reality that they're not just kinase or protease (i.e. target) inhibitors, they're also inhibitors of cancer, which is definitely a phenotype.

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23. Anonymous on April 18, 2012 7:11 PM writes...

Derek's post mentions reviews categorizing the earlier phenotypic screen era as so much more productive than the more recent target-based approaches have provided, but there are so many more hurdles in place now that didn't exist then. Would the drugs that came to market during the phenotypic screen heydays also make it through now? Are there phenotypic screens that would result in the cautious approaches to the clinic that the data from molecular biology-based hERG and CYP induction assays provide? I haven't read the synopses referred to, but do they incorporate the drugs later pulled from market, or those that effectively go un-used when liabilities are identified post-approval by FDA?

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24. Anonymous on April 19, 2012 3:10 AM writes...

There seems to be some confusion above between using phenotypic screens to give you CIR and phenotypic screens to drive SAR. You need to think about what you are arguing for/using the data for - the two things do not need to be linked and confusing the two is not helpful. However, I think the discussions above do demonstrate the pros and cons of using phenotypic screening well.

I think there was a review in Nature Reviews last year on how drug targets were discovered. Pheno screens were credited with more success in general but this could be because more have been done historically (however, they didn't go back that far). Interestingly, cancer was the area where target based approaches appeared to have more success. Again, this may just because more have been discovered recently leading to a bias but I can't help but wonder if diseases where you need to 'shut down pathways to stop growth/replication' (eg cancer, virals) are better approached by target based methods while others where you are trying more subtle re-balancing of homeostatic mechanisms need to be approached more from the pheno angle to get you on the right path???

@18 Rick, love your comments but I thought I would put my experience of 1. into the mix. The problem about toxicities and unknown MoA is how do you trust your safety models are modelling the target? More importantly, how do you convince the regulators. I have been to more regulatory meetings than I care to remember to discuss this and their view never wavered from the 'if you don't know the MoA we don't trust your safety data and you can't go into man. Period'.

Also, How often does mechanism of toxicity of a drug have anything to do with its mechanism of action? All the time - you've obviously never dosed high enough because you have seen other off-target effects first (no window). Just about every drug has on target tox effects. 'Every drug is a poison, it is just a question of dose'.

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25. Rick Wobbe on April 19, 2012 8:36 AM writes...

#24, Anonymous, Thanks for your excellent feedback. I'm familiar with the regulatory meeting scenario you described and it is unfortunate because it doesn't seem pharmacologically justified. It's interesting that FDA guidance documents seem to downplay or ignore the situation, but maybe that's because people who think about the situation differently write them. I've been reviewing drugs that were withdrawn from the market for safety reasons since the 1960s and I've begun adding drugs that were not granted NDAs for safety reasons covering the same period and the trend seems to be that toxicity is "off-target" in the vast majority of cases. (For an earlier published review of withdrawn drugs check out Wysowski, DK and L Swatrz (2005) Arch. Int. Med. 165: 1363-1369, which supports the same conclusion.) Therefore, although I agree that the regulatory meeting situation you described arises disconcertingly often, there seems to be no objective, data-driven reason for distrusting safety data for drugs if a mechanism of action isn't hypothesized. I hope that data will eventually dispel the distrust.

I think your second paragraph supports my point: the dose response curves of dose-limiting toxicity, which are almost always "off-target", peak long before the dose response curves of on-target or "on-target homolog" toxicity. Thus the illogic of either alternative of a statement like "This compound is a bacterial topoisomerase inhibitor, therefore it [does/doesn't] cause QT prolongation." That's not to say that counterscreens against homologs of your target that you don't want to hit are totally worthless. (God knows I've run plenty of them myself and they support the "every drug is a poison..." maxim.) They can help get rid of junk compounds that'll screw up anything (e.g. Michael acceptors, chelators, detergents), but I've also learned that those things are almost always detected in other, usually cheaper (!), downstream tests (e.g. cytotoxicity) or screens that colleagues at neighboring benches are running too. Yes, there are rare exceptions, mu opioid receptor antagonists like propoxyphene that cause QT prolongation, but that rareness quantifies the extent to which fingering a target does not inform tox.

My bottom line is that if you look at historical data over any time period you want, having a proposed target actually does less to help with "Mechanism-based toxicity" than people generally think. Moreover, by redirecting the focus of limited resources away from other important activities, putting unnecessary emphasis on mechanism of action in the belief that it'll help with toxicity evaluation or that it somehow mitigates toxicity concerns is actually a bad thing. To put it more bluntly, a significant fraction of the time we spend on mechanism of action might be better spent using many of the same biochemical and molecular biology tools to investigate toxicology. I would love to hear more of your thoughts about this, but this may not be the right forum. If you want, you can look me up on LInkedIn.

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26. Cellbio on April 19, 2012 9:34 AM writes...

Late to the show here, but a few comments:

#14, the target approach does screen in cells to make sure the compound "does what I want it to", but that is part of the problem. Working within an excepted paradigm of what a compound does based upon its known affect on one target is wildly misleading. properly executed cellular phenotypic screening of a target-derived compound, that is screening many diverse assays that have relation to what the project leader wants the compound to do, reveals that no single pharmacology is associated with a large panel of compounds (have done this for many versions of approved drugs, and with thousands of leads). In other words, there is a phenotypic variance that is unexplained by a molecular target. Therefore, selecting compounds without this information leaves one ignorant of variable pharmacology, and carrying forward into Development the same unknown risk critics point to for compounds without a target. Not knowing this does not make it less likely to sink your compound.

Gleevac is a good example of the polypharmacy driven phenotypic response that is often associated with "target" compounds. Many more out there, probably BTK compounds too, that show how driving for selectivity would not yield efficacy, and driving forward with a less then "perfect" target compound was productive. Starting with a target is OK. Accepting the paradigm of a compound being a fill-in-the-blank inhibitor because it was found with a target screen is a problem. Notice how the Pfizer JAK3 compound is now a JAK inhibitor? A nice story of selectivity driving efficacy and safety is not required now that there are clinical responses.

To other comments, an integrated response...

SAR can be developed, and should be used to elect compounds and distinguish from potential drug-like pharmacology and toxicology/stress. Similar to target based efforts, no difference at all conceptually, one has to validate a tox species. I argue, having a pharmacological signature, such as inhibits processes 1,3 7, and 9, but not 2, 4-6, 8 and 10, is more rigorous than showing binding to a target. So one can show the pharmacology translates to tox species with similar potency, though there are limits of ease depending on therapeutic area.

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27. Ray Perkins on May 6, 2012 7:22 AM writes...

There is a middle pathway. As background for this comment, we all should realize that genotypically-derived targets have not been confirmed by other methods. Ergo, many, if not most may be irrelevant or simply wrong. In a middle pathway, genotypically-derived potential targets serve not as endpoints but as indicators for more exhaustive, bio- and pharmaco- relevant testing. Thus the best of both pathways are preserved but placed in realistic context. We address this in our "Drug Interactome" approach to target development and candidate screening.

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28. Ha ha ha on May 6, 2012 1:50 PM writes...

I agree with most comments where phenotypic screens do not offer any specific advantages over target based therapy. Well, I think the major assumption in target based therapy is a 'single target' which is not really true in taking complexity of biology into context. My belief is the disease process is not one day process and several multiple insults resulting in damage that precipitates as disease. This whole process may take years before disease manifests as life threatening disorder. One really need to know what is the first initiating process in disease induction butunless we understand the functional genomics we will not make much process in target bases therapy. The sad part today in drug discovery research is cookie cutter approach trying to run to clinical trials without clearly translating preclinical data to useful clinical data. As lon as we adopt a rat race approach to become instant multi millionaires we will not succeed in drug discovery research. Basic research should be conducted for a few years before embarking on futile clinical trials.....

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29. DFW on May 13, 2012 8:49 AM writes...

Thank you all for a very interesting thread of comments. My background is in PK and where most of my career has been spent, but recently accepted a position leading nonclinical Pharmacology and DMPK organizations. I see real advantages in having both groups working closely together to improve translation of phenotypic data to clinic. Simple details, like formulation, can be coordinated for both studies and provides greater assurance of consistent concentration-time course of drug. Often times studies can be combined, saving resources, and increasing the robustness of data. These studies are not as simple to conduct, and in large separate organizations become difficult often for political or territorial reasons. I am hopeful that when phenotypic pharmacology is combined with quantiative, math driven PK/PD, predicting doses for clinical phenotypic studies is improved. I have revisited some recent clinical failures in neurology from large organizations, and found that there was a disconnect between nonclinical and clinical drug exposure. This wasn't for lack of very good scientists in DMPK or in Pharmacology, and appears more to be a disconnect in communication between functions.

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