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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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« Standard of Care? Not So Fast, Not in the United Kingdom | Main | Not What It Says On the Label, Though »

February 27, 2013

Selective Inhibitor, The Catalog Says

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Posted by Derek

There's an interesting addendum to yesterday's post about natural product fragments. bAP15.pngDan Erlanson was pointing out that many of the proposed fragments were PAINS, and that prompted Jonathan Baell (author of the original PAINS paper) to leave a comment there mentioning this compound. Yep, you can buy that beast from Millipore, and it's being sold as a selective inhibitor of two particular enzymes. (Here's the original paper describing it). If it's really that selective, I will join one of those Greek monasteries where they eat raw onions and dry bread, and spend my time in atonement for ever thinking that a double nitrophenyl Schiff base enone with an acrylamide on it might be trouble.

Honestly, guys. Do a Ben Cravatt-style experiment across a proteome with that think, and see what you get. I'm not saying that it's going to absolutely label everything it comes across, but it's surely going to stick to more than two things, and have more effects than you can ascribe to those "selective" actions.

Comments (20) + TrackBacks (0) | Category: Chemical Biology | Drug Assays


1. nitrosonium on February 27, 2013 9:39 AM writes...

Amazing!! i was scared that just looking at this structure would lead to alkylation of every lysine and in my body....for starters

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2. partial agonist on February 27, 2013 9:53 AM writes...

It only inhibits anything at all with a lysine or or cysteine in it, or anything having any other biological nucleophiles present such as DNA bases.

Sheesh, if ever there was a "hit" to ignore completely, that one is it. 3 Michael acceptors?

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3. opsomath on February 27, 2013 9:58 AM writes...

Selective to what? Nucleophiles?

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4. Dan Erlanson on February 27, 2013 10:12 AM writes...

According to the journal homepage this article has been cited more than 20 times, so who knows how many people have been misled.

One positive development is that researchers trying to reproduce published results are increasingly reporting the artifacts; a nice recent example from Ariad on LDHA inhibitors came out in J. Med. Chem. earlier this year (click on my name in the comment heading to see the discussion on Practical Fragments).

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5. imatter on February 27, 2013 10:12 AM writes...

Millipore also described it as reversible.

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6. Hap on February 27, 2013 10:22 AM writes...

Well, duh - just hit the cell with NaOH and a thiol and it'll retro-Michael off whatever protein it labeled.

I'm guessing that's not what they meant, though.

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7. brian on February 27, 2013 10:23 AM writes...

It's not a Schiff base though. There's no carbon-nitrogen double bond.

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8. newnickname on February 27, 2013 11:47 AM writes...

The acrylamide is scary. (Wasn't there a report of acrylamide being formed in the normal deep frying of french fries a couple of years ago?) But the cross conjugated dienone doesn't look as bad as it looks ... if you get what I mean by that Yogi Berra-ism. It is an arylogous (cf, vinylogous) beta-nitro-enone and probably not nearly as polarized for Nu attack as a simpler enone. Corey, Danishefsky and others have looked at which group is more powerful at controlling directing effects in beta-nitro-enones and analogs.

If I had some easy software (Spartan?) handy, I'd look at the polarity of those double bonds with and without the nitros.

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9. Nate on February 27, 2013 11:56 AM writes...

The nitros will probably have fun inactivating various ALDHs.

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10. VP of research on February 27, 2013 12:30 PM writes...

I'd like to inlicense this as a clinical candidate. What's your asking price?

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11. Hap on February 27, 2013 12:46 PM writes...

Oh, and as if there weren't enough Michael acceptors, 4-piperidinones are Mannich-type adducts. With the amide on N, addition to the benzylic carbon of either nitrobenzylidene group will likely generate an enolate which can retro-Michael the acrylamide moiety and generate a nice alpha-methylene ketone (similar to a Baylis-Hillman adduct). Theoretically (since I don't know and am not confident that it acts this way under in vivo conditions), it could be a five-fold Michael acceptor (acrylamide + four-fold addition to nitrobenzylidene methylene ketone).

The aryls probably add hindrance and stabilize the enones, but the nitro groups probably reduce the stabilization some (since they're EWG and the enone is already electron-deficient). It's not like the nitros are stuck directly on the olefins, but I don't imagine they help. Reducing the nitro groups would stabilize the enones, but losing the enone at the cost of two anilines might not work out so well.

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12. Anonymous on February 27, 2013 1:25 PM writes...

Ugly molecule; NIH funded it, a faculty got his tenure, a student graduated PhD, and what else are the damages?

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13. darwinsdog on February 27, 2013 2:52 PM writes...

"selective" in a catalog is similar to its use in a patent filing. With regard to the above and speaking as someone who has done directed activity-based probe experiments including inhibitor focusing (am I blowing my cover ;-) it could also likely be billed as a glutathione scavenger, tubulin binder etc

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14. SP on February 27, 2013 4:20 PM writes...

@12- Wow, the NIH is funding research in Sweden? That is problematic. And the authors didn't even mention an NIH grant- ungrateful bastards!
How about you make sure you know what you're talking about before belching out nonsense?

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15. Anonymous on February 27, 2013 7:29 PM writes...

Well - think about this, who would have thought that "dimethyl fumarate" could be used as a drug...??

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16. Trollumination on February 27, 2013 10:07 PM writes...

Here's the logical next question - how many ACTUAL drugs, commercially available and used in medical practice, are PAINS themselves? I'm not a medchemist but I can think of the nitrogen mustards off the top of my head. Anon #15 points out dimethyl fumarate.

How many real, common, useful drugs out there are PAINS? It does matter. If HTS discovery has to avoid such compounds, and if such compounds are often clinically useful, then a Bayesian perspective on the efficacy of HTS versus old-school guessing might be valuable. If modern methods couldn't discover the drugs our ancestors developed, well, maybe it's step forward, step back.

"Hate was just a legend
And war was never known
The people worked together
And they lifted many stones.

They carried them to the flatlands
And they died along the way
But they built up with their bare hands
What we still can’t do today."

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17. Hap on February 28, 2013 1:14 PM writes...

Lots of anticancer drugs. Acetaminophen's been noted as a problem, though it doesn't immediately have the reactivity this one probably does. Most of the complaints about past drugs are Ro5 compliance, though, and not reactivity, because even though people's tolerance toward hydrophobicity and size have changed, chemical reactivity (and its biological consequences) really haven't.

Probes in theory need to perform with higher selectivity than drugs - in drugs, positive off-target effects are a feature, not a bug, but when you're wanting to know exactly what is occurring in a biological system, any off-target effect is a bug. This has lots of potential to react with lots of different things, and while some of Cravatt's work indicated that chemical active-site probes can be more selective than you'd expect, you don't want to base your drug development research on a vigorous game of electrophile roulette.

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18. Whatevs on February 28, 2013 8:54 PM writes...

Aw Derek, why you discrima-hatin' on Cravatt? (Just kidding!)

Just slap that sucker onto an antibody and voila, you got an ADC! (ADCs are en vogue, right?) If Pfizer/Wyeth can find a way to synthesize large amounts of calicheamycin-containing ADC, applying this compound should be a cake walk.

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19. Secondaire on March 1, 2013 10:37 PM writes...

Dear God, this thing looked like it would bite you if you poked it with a stick. It almost reminds me of piperlongumine, a similar poly-acrylamide Michael acceptor cherry bomb:

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20. Anonymous on March 21, 2014 10:54 AM writes...

Here's a classic PAINS compound for LSD1 - or as XCessBio would like you to believe, "LSD1-C12 is a highly potent, specific, and reversible Lysine Specific Demethylase-1 (LSD1) inhibitor"

Worrying that a) This compound got into JMC without much of a struggle (talk about lax reviewers - paper talks about protonated morpholino sulfonamides?!).

b) It's now being sold to unknowing scientists, wasting their time.

c) It almost got into clinical trials (in children at that!) thanks to a $1.7 million charitable donation.

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