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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

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August 3, 2012

Finding Fast Fruit Fly Feasibility

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Posted by Derek

I'm an unabashed fan of phenotypic screening. (For those outside the field, that means screening for compounds by looking for their effects on living systems, rather than starting with a molecular target and working your way up). Done right, I don't think that there's a better platform for breakthrough drug discovery, mainly because there's so much we don't know about what really goes on in cells and in whole organisms.

Doing it right isn't easy, though, nor will you necessarily find anything even if you do. But there's a recent paper in Nature that is, I think, a model of the sort of thing that we should all be thinking about. A collaboration between the Shokat group at UCSF and the Cagan group at Mt. Sinai, this project is deliberately looking for one at the trickiest aspects of drug discovery: polypharmacology. "One target, one drug" is all very well, but what if your drugs hit more than one target (as they generally do?) Or what if your patients will only be served by hitting more than one target (as many diseases, especially cancer, call for)? The complexities get out of control very quickly, and model systems would be very helpful indeed.

This work goes all the way back to fruit flies, good ol' Drosophila, and the authors picked a well-characterized cancer pathway: multiple endocrine neoplasia type 2 (MEN2). This is known to be driven by gain-of-function mutations in the Ret pathway, and patients with such mutations show a greatly increased rate of endocrine tumors (thyroid, especially). Ret is a receptor tyrosine kinase, and the receptor is one that recognizes the GDNF family of signaling peptides. As oncology pathways go, this one is fairly well worked out, not that it's led to any selective Ret inhibitor drugs so far (although many have tried and are trying).

Using this Ret-driven fly model, the teams ran a wide variety of kinase inhibitor molecules past the insects, looking for their effects, while at the same time profiling the compounds across a long list of kinase enzymes. This gives you a chance to do something that you don't often get a chance to do: match one kind of fingerprint to another kind. And what they found was that you needed "balanced polypharmacology" to get optimal phenotypic effects. The compounds that inhibited the Drosophila equivalents of Ret, Raf, Src and S6K all at the same time made the flies survive the longest. That's quite a blunderbuss list. But some very similar compounds weren't as good, and that turned out to be due to the activity on Tor. Working these combinations out was not trivial - it took a lot of different strains of flies with different levels of kinase activity, and a lot of different compounds with varying profiles.

Now, these kinases cover an awful lot of ground, as you'll know if you've worked in the field, or if you just click on those links and look at some of the pathway diagrams. There is, I think it's fair to say, no way that anyone could have identified these particular combinations with certainly without running the experiment in a real system; there are just too many branching, intersecting, ramifications to get a clear picture of what would happen. Thus, phenotypic screening: let the real system tell you.

So, you may be thinking, fruit flies. Great. Does that tell us anything real? In this case, it looks like it does. The compound profiles that were seen in the model system translated to human cell lines, and to mouse xenograft models. And while neither of those is a perfect indicator (far from it), they're about the best we have, and many are the compounds that have gone into human trials with just such data.

I look forward to more applications of this technique, to see how far it can be pushed. Ret looks like a well-chosen test case - what happens when you go on to even trickier ones? It won't be easy, but being able to unravel some of the polypharmacology when you're still back at the fruit-fly stage will be worth the effort.

Comments (9) + TrackBacks (0) | Category: Cancer | Drug Assays


1. Rick Wobbe on August 3, 2012 8:40 AM writes...

In focusing on always bringing everything back to a molecular mechanism/target of action, let's not forget that phenotypic screening is immensely valuable in identifying potential toxicities and their mechanisms simultaneously. It's certainly better suited for the job than target-based screening. Polypharmacology is not just about hitting what you think you need to hit, it's also about avoiding what you surely need to avoid!

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2. darwinsdog on August 3, 2012 10:58 AM writes...

I agree with the comments on phenotypic screening BUT the challenge with high order multi-targets (not talking just 2 or 3 targets) is you can't optimize easily so the hit ends up having to be drug which is a high hurdle. Ex. Multi-kinase inhibitors are known to be drugs but if you look back at their development, their poly-target nature was not fully appreciated in early development (i.e. we realized the luck only retrospectively).

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3. polybus on August 3, 2012 2:11 PM writes...

What about cocktails where each component aims for a different target, akin to HAART?

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4. darwinsdog on August 3, 2012 4:20 PM writes...

poly, combination regimens are a completely diff. animal from a regulatory perspective. Long the domain of infectious you are seeing oncology talking about them as I think was commented on here a few days ago ( )

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5. anonymous on August 3, 2012 7:22 PM writes...

Beg to differ w/ you - you optimize using the phenotypic screen (

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6. TX Raven on August 4, 2012 7:02 AM writes...

... and how exactly are we linking these effects to human?

How would we know that whatever polypharmacy works best in a fly, will work best in human?

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7. Crimso on August 4, 2012 9:38 PM writes...

TX: we won't know until we try; which is why I am constantly cautioning my students that when they read of a promising new cancer treatment, to ignore it until it is shown to actually have an effecct in humans.

That having been said, the reductionist approach of looking for compounds to target specific enzymes is certainly still useful (it's not an either/or situation). The work discussed in this post, though, indicates that phenotypic screening is more likely to get you a good drug.

There are many reasons to continue to pursue drugs targeted to specific enzymes, not the least of which is the fact that examining the mechanisms of these drugs can tell us a lot about how the enzyme normally functions. That may not "cure cancer," but it might just end up putting the final piece of a puzzle in place that eventually does lead to a better drug.

Think of all the hurdles your drug has to clear, no matter how fantastic it looks against the purified target. Does it get into the body? Does it persist in the body (long enough but not too long)? Does it get to the tissue you're targeting? Does it get into those cells? Etc. etc. etc.

Again, I will stress that I am not against studies with purified enzyme (it's what I do, or at least used to, before teaching; still try to sneak some in). Sorry for the jumbo comment. Great post.

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8. Anonymous on August 6, 2012 9:14 AM writes...

@3 - cocktails would be nice. but till date ultra-specific in-vivo inhibitors have not been found. they all bring additional target inhibition (and tox therefore)...multiply that by the no of nodes you need to inhibit and you create a major problem.

having them potentially in one or two molecules could cut down on the tox. which is what seems to be in this case.

And all of this boils down to phenotypic screening, which I think is key.

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9. ChemBob on August 6, 2012 12:38 PM writes...

Our lab is starting to use zebrafish as a cheap model for this as well. Not quite fruitfly cheap, but the lowest cost vertabrate model I'm aware of

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