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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: Twitter: Dereklowe

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January 8, 2014

A Tool Compound's New Personality

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Posted by Derek

Here's a paper that may require some recalibration in the existing literature. It reports that a widely-used tool compound LY294002, known as an inhibitor of the PI3 kinases, is also a bromodomain ligand. There seems little doubt that some of its cellular effects, depending on the assay conditions, could be due to this mode of action, rather than its kinase activity. Putting "LY294002" into a PubMed search gives you, as of this morning, 7075 hits, so surely some of these results have been muddied up a bit.

PI3K and the BRD bromodomain family are, as you'd figure, structurally unrelated, but that doesn't stop things like this from happening. Time and again, tool compounds that have been accepted as acting on System A have turned out to also hit System B, and when system Z gets discovered, turn out to hit that one, too. The point is, there are a *lot* of ligand binding sites out there, and to assume that a given compound only hits the one that you know about is unwarranted. Now, at the same time, very little progress gets made if you assume that there are no tool compounds at all, so the only thing to do is proceed alertly, and be ready to revise your conclusion. Which is how we're supposed to be working, anyway, right?

Comments (18) + TrackBacks (0) | Category: Chemical Biology


1. bhip on January 8, 2014 9:47 AM writes...

Thanks Derek- helpful. That said, I doubt it will disabuse the continued use of the compound as a specific inhibitor of PI3 kinases. The pervasive use of dirty compounds as proof-of-concept/mechanism really is remarkable, both in academics & Pharma. Keep an eye out for the claims of "inhibition of PLC with the inhibitor, U73122", "PKC inhibition with staurosporine", etc. in publications or (even better) in Team Meeting presentations at your local pharmaceutical company.

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2. Mark on January 8, 2014 11:12 AM writes...

Will this have any impact on the PI3K inhibitors in clinical development? Or does this type of finding only affect the preclinical research environment?

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3. Anonymous on January 8, 2014 11:13 AM writes...

Everybody in the field already knew that the LY compound was a very dirty inhibitor of PI3K. There are many newer, better ones. Interesting to know at least one of the undoubtedly many other proteins that it also inhibits, but the general idea that LY was a dirty compound is very old news.

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4. anon the II on January 8, 2014 12:26 PM writes...

Anytime I see a chromone or a coumarin in a lead structure, I quickly note the lab and turn the page, scroll down or hit the back button to avoid wasting anymore time thinking about it.

I guess I made an exception today, taking time to post this.

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5. Cellbio on January 8, 2014 12:52 PM writes...

anon the II,

Had fun once when called in to meet with potential execs and founders of 'new company to be' because they had awesome data for great indication, tons of buzz, ....then at about slide #60, the structure, a coumarin compound. I asked what had they measured outside of the biology of interest, nothing. I had fun creating a list from the literature and had at least a dozen indications for such compounds, anti-cancer, anti-parasite, anti-microbial, anti-inflammatory..... in essence, incompatible with biochemical processes associated with life.

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6. ScientistSailor on January 8, 2014 1:05 PM writes...

The PARP inhibitor PJ34 is also dirty as heck, take any of the cellular data generated with this molecule with a large grain (boulder) of salt...

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7. partial agonist on January 8, 2014 1:15 PM writes...

Anyone who applies the term "tool compound" to a molecule for which no significant deck of selectivity data exists is misusing the term.

"The first reasonably potent ligand known to act at this target" is the unwieldy but way more accurate term to use.

A tool compound to me anyway implies it has a degree of certainty for its mechanism of action and target vs. off-target activity, such that it can be used in efforts to validate whether the target in question is even worth studying.

It doesn't even mean that the tool compound itself is terrifically potent. Selectivity is likely much more important for target validation.

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8. JSR on January 8, 2014 1:20 PM writes...

I came here today to see if Derek had talked about this paper:
Rational Design of a Structural Framework with Potential Use to Develop Chemical Reagents That Target and Modulate Multiple Facets of Alzheimer’s Disease

That's like making a nightmare ON PURPOSE! Sheesh. Academic drug discovery at its finest.

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9. Petros on January 8, 2014 1:40 PM writes...

Re #8

Fig 1 of that paper rams home the point

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10. Anonymous on January 8, 2014 2:47 PM writes...

using any tool compound with a micro molar IC50 is asking for trouble-it will very likely have additional 'targets'. The surprise is....?

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11. anony-mous on January 8, 2014 7:14 PM writes...

Hmmm....let's consider your comment for a moment, shall we? Let's say we have a (reasonably / quite?) selective compound that hits our intracellular target protein "inhibitmease" with a Kd of 1--10 nM. Now lets say that selective inhibitor is 99.9% protein bound in 20% serum (not at all uncommon) that we use in our cell based assay to keep our cells happy. Wouldn't we expect a cellular EC50 in the 1--10 uM range in such an assay? Would the use of such a compound at 1--10 uM REALLY be asking for trouble via "off target activity" (remembering that only 1--10 nM of the compound is free)? I'm not convinced !

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12. Lunar Landing on January 8, 2014 9:07 PM writes...

Few molecules that flat and simple will be selective. In addition, I will not be surprised to learn that many molecules interact with epigenetic targets. These proteins need to be incorporated into cross selectivity screens such as cerep assays.

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13. Mfernflower on January 8, 2014 9:26 PM writes...

That molecule looks like death on a stick.
I see problems on the quinoline and the idea of that fitting into a DNA strand makes me fell ill. There's also multiple sites that could reduce iron and do the exact opposite of what the wanted it to do. - Generate free radicals. That structure looks like the proposed free radical toxin produced by Pifestria!!!!!!!!!!!!!! The steric framework of the whole molecule itself already look like its not going to make it past lab mice. I do computational simulations and for shits and giggles I made a hell of a DNA intercalating agent! (Its a derivative of aristcholic acid)
The smiles is as follows:
WARNING! This is horrifying and worse than the chromene compound that Lilly decided to make real! Or even that mess that #8 showed me! But now my mind wonders how on earth was that put into a journal and if I could get my baby into one! >:D

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14. Jay Bradner on January 8, 2014 9:54 PM writes...

Thanks Derek for the post. Since our 2010 report of the JQ1 BET bromodomain inhibitor we have seen numerous pharmacophores bind the acetyl lysine pocket, in our lab and especially in the literature. So much more to follow here for sure. I am curious what the community here recalls as the target(s) engaged by the most structurally diverse inhibitors? BETs must be among them. Magnets I tell you. Best. Jay

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15. Kid on January 9, 2014 1:21 AM writes...

Sigma-1 receptor binds most things you throw at it.

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16. Anonymous on January 9, 2014 7:02 AM writes...


Tubulin is up there. Every HTS I have seen seem to have 1-5% of compounds in the library bind tubulin. Could be the most common hit of DOS libraries., esp. since they are typically quite hydrophobic which tubulin loves.

BTW, without a drug resistant allele for your 'tool' compounds everyone, there will always be the question of whether the phenotype you are seeing in cells/animals is due to is intended target(s). The best, most useful and believable compounds have that. The best journals should demand it. This is very much the case for so-called 'nM inhibitors' where PK is ok but you still need 100 mg/kg to see phenotype. Good chance at that dose you are hitting all kinds of stuff.

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17. Mfernflower on January 9, 2014 11:00 AM writes...

@16 Yes, it seems like that is a common QSAR thing. It seems as if any big hydrophobic macrocycle can do the trick. just provide a few oxygen's and you got a tubulin inhibitor :D

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18. melanotan 2 on October 23, 2014 5:49 PM writes...

These can be detected continuously, allowing peptides the epidermis due to the skin.

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