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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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February 19, 2010

Two For One Sale

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Posted by Derek

A double complaint this morning, and both from the same literature item - if I were charging anything for the blog, I'd say that it's delivering value for the money. At any rate, the first kvetch is something that I know that many chemists have noticed when reading more biology/medical-oriented journals. You'll see some paper that talks about a new compound that does X, Y, and Z. It'll be named with some sort of code, and they'll tell you all about its interesting effects. . .but they don't get around to actually telling you what the damned stuff is.

As I say, this is a chemist's complaint. Many biologists are fine stipulating that there's a compound that will do these interesting things, because they're mostly interested in hearing about the interesting things themselves. It could just be Compound X as far as they're concerned. But chemists want to see what kind of structure it is that causes all these publication-worthy results, and sometimes we go away disappointed.

Or we have to dig. Take this PNAS paper on a broad-spectrum antiviral compound, LJ001. It looks quite interesting, with effects on a number of different viral types, and through a unique mechanism that targets viral membranes. But what is it? You'll look in vain through the whole paper to find out - that compound is LJ001 to you, Jack. You have to go to the supplemental material to find out, and to page 10 at that.

And that brings up the second complaint. LJ001 turns out to be a rhodanine, and regular readers will note that earlier this month some time was spent here talking about just how ugly and undesirable those are. It's very, very hard to get anyone in the drug business to take a compound in that class seriously, because they have such a poor track record. Looking over the small SAR table provided, I note that if you switch that thioamide group (the part that the chemists hate the most) to a regular amide, turning the thing into an thiazolidinedione, you lose all the activity.

TZDs aren't everyone's favorite group, but at least they've made it into marketed drugs. Rhodanines are no one's favorite group, and it would be a good thing of the authors of these papers would realize that, or at least acknowledge it if they do. It's not an irrational prejudice.

Comments (32) + TrackBacks (0) | Category: Drug Assays | The Scientific Literature


COMMENTS

1. Caleb on February 19, 2010 10:35 AM writes...

I was at a talk this morning where the presenter was discussing a new enzyme inhibitor-a hemiaminal of ninhydrin. Put it into aqueous solution and boom, there's your enzyme inhibitor. Thankfully they discovered what was going on, but had they not shown the structure to a chemist...

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2. RB Woodweird on February 19, 2010 10:46 AM writes...

The paper is from The Ohio State University (as their pitskin-toting alleged alumni say). None of the authors are the least interested in the potential marketability of the mysterious LJ001, nor are they going to care about the needs of the industrial medicinal chemist. They are only after the publication as a publication so 1) the graduate students can write up and get out, 2) the postdocs can revise the CV, and 3) the PIs can forward the link to their tenure committee.

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3. Big D on February 19, 2010 10:51 AM writes...

Hey Derek have you read this paper? "Rhodanine as a Privileged Scaffold in Drug Discovery" Current Medicinal Chemistry, 2009, 16, 1596-1629. We have some rhodanines in our current screening library and I think we see hits from them in every screening assay we run.

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4. Hap on February 19, 2010 11:18 AM writes...

There seems to be a lot of lack of explicitness of compounds and their synthesis in med chem (letters, particularly) - in lots of cases, the authors don't seem to have any idea that someone might want to reproduce the work and so knowing how they made their compounds and what they did would be helpful. With the presence of online SI for most journals, there isn't a good reason not to put the details of synthesis and testing somewhere (not wanting to take the time to write them or not being able to find the details aren't good reasons, alas). If people want to read them, they can, and if people are just interested in the activity, well, they don't have to read it. Having a compound that isn't good for anything other than a publication is just icing.

OSU isn't that bad, in fact, for chem - they have/have had some pretty decent people (Hart, RajanBabu, Paquette, Stambuli, in organic, for example). There are lots of reasons to dislike OSU, but I don't think their science is actually one of them.

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5. Hap on February 19, 2010 11:20 AM writes...

I meant Parquette when I wrote Paquette (Paquette's good but I thought he was semi-retired - Hart as well), but that doesn't exactly hurt the point.

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6. Keith Robison on February 19, 2010 11:27 AM writes...

AHEM! Biologists want to figure out what it is too, if only to pass on to the chemists who can tell them how interesting the chemistry is (or is not)

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7. Cellbio on February 19, 2010 11:33 AM writes...

Well, this biologist joins you in the complaint, maybe because I started as a molecular biologist.

I think there is also a connection to yesterday's post about numbers, or thinking of biology in a quantitative way. Often, biologists of the non-molecular nature put little to no value in determining and evaluating a concentration-effect relationship.

I think we need to restore classic disciplines, such as pharmacology, to remedy this problem. Biology today follows gene knock-out mentality too much....with gene, one behavior, without another.

When asking a biologist once why she decided at the last minute to up the concentration of test agent to 60 uM, despite my very different recommendation, the answer was, 'Well, I wanted to make sure we saw an effect'. Yah, that ought to do it.

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8. partial agonist on February 19, 2010 11:34 AM writes...

As someone who hates wasting time following up HTS leads that don't ever evolve into drug-like molecules, I'd prefer to purge all of the rhodanines, polyphenols, reactive molecules, and Russian pesticides from screening decks that are used for any target I ever work on.

It never fails- the biologist gets all excited about a result and the compound is a derivative of gossypol and I have to explain why having a whole buch of aldehyde groups and phenols in the same molecule makes it unappealing to me, no matter what the biological result.

I am also constantly annoyed when the first papers that come out in an area tout the exciting properties of a new compound and all you ever learn is its code name. Ugh. Part of the game of covering it up. Some companies get their compound into the clinic without ever specifying the structure and everyone in the field has to make educated guesses from reading the patent examples.

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9. Anonymous on February 19, 2010 11:46 AM writes...

A standard trick is to promise that the structure of the drug will be revealed in a second paper, and then never publish that second paper.

One example (among many) is Torin-1, an mTOR inhibitor discovered by Nathanael Gray's lab at Harvard and published in JBC over a year ago. The compound is widely-discussed in the literature, but the structure has never been disclosed.

Journals should not allow this.

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10. anchor on February 19, 2010 12:11 PM writes...

Rhodanine and its ilk thioamides and thioureas in my humble opinion are very promiscuous lead compound and show up everywhere in all HTS assay. As a chemist I would be cognizant that if the list or lead contain these entities, it should raise a red flag. Never mind that people where I worked belted out one analogs after another, have been reawarded and then subsequently failed.

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11. Fries With That? on February 19, 2010 12:29 PM writes...

No,No No! you have it all wrong. See, the biologists hide the structures because they want to license the drug and become millionaires, I tell you! Mega-multi millionaires.
When your average stupid biologist (such as myself) sees how much time and effort patent writers use to bury their active structure in a miasma of structure after structure after....
well, you get it.

I mean, for heaven's sakes, why make it easier on your competitors/thieves?

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12. NJBiologist on February 19, 2010 12:41 PM writes...

@9: "Journals should not allow this."

Some don't. I think all the FASEB societies' journals have a standing order that thou shalt not publish if the structure isn't available to the public (that would include JPET, Mol Pharm, DM&D, etc.). This probably gets at the issue @6 and @7 were leaning toward--if you're thinking a paper points the way toward a proof-of-concept for a program, you're going to need to reproduce the structure.

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13. Anonymous on February 19, 2010 2:01 PM writes...

The widespread prevalence of not revealing chemical structures in the biological literature is completely scandalous. Forget competition, exciting biological results, whatever. We are all scientists, and a key tenet of the scientific method is: the hypothesis must be be testable. Not disclosing the structure makes it impossible for another lab to attempt to reproduce the work. Not that anyone would ever want to do that, because everything that's published is completely reliable and mistakes are never made-- right?

Keeping your structures close to the vest is just bad science, pure and simple. If you want to obscure your pet structure, keep to the patent office. Don't pass it off in a peer-reviewed journal as if it's actually science.

FWIW, I don't think that most of this bad behavior stems from a great desire for secrecy. I think it comes mostly from biological ignorance of chemistry. Can't tell you how many biologists I've spoken to who have no clue why a structure in a paper would matter to anyone. Maybe if there were a few more medicinal chemists in the peer review pool and editorial boards of some of these journals, awareness could be raised and this kind of bad science could be stopped.

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14. Anonymous on February 19, 2010 2:39 PM writes...

@13

I think that not only the structure, but also some purity data would be helpful. Great results from XXXX8934, where the activity comes from a 5% of ultrapotent impurity, are pure crap.

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15. chris on February 19, 2010 2:39 PM writes...

Referees should insist the structure is included.

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16. Hap on February 19, 2010 2:50 PM writes...

Knowing how it's made would also help others to figure out what impurities might generate the data if it's not the major compound - making the compound by a different route wouldn't necessarily generate the same impurities, and so might give different activity.

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17. scientist on February 19, 2010 2:52 PM writes...

It isn't science if the paper doesn't give enough detail to evaluate and replicate the results. Compound X all too often smells like week old fish when you do get to sniff the structure. Nature Chemical Biology's current issue has a series of commentaries on 'probes' that attempt to educate & set a standard. Comes down to journals having decent referees & standards.

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18. jerseyjerk on February 19, 2010 6:31 PM writes...

If the reviewer's idenities were published with the authors in these "high impact" publications, does anyone think this nonsense would decrease?

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19. J-bone on February 19, 2010 6:44 PM writes...

I'd love to fleece reviewers who don't do their job, but a public outing will never happen. Not ever.

I maintain my stance that the fastest way to overhaul peer review is to hide the author names from the reviewers. That will keep people from immediately ushering their friend's manuscript through or being swayed by a bigwig's name on the end of the author list.

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20. Carmen on February 20, 2010 10:01 AM writes...

I've always found it amusing that at some "first disclosure" talks, different slides (rapidly advanced of course) portray the compound in different orientations- you've gotta work fast to get that structure down.

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21. CanChem on February 20, 2010 10:10 AM writes...

@19

I disagree with hiding author names from reviewers; if it's a bigwig's paper you can usually tell by the abstract from their chemistry and writing style, and if it's a friend you'd know from the chemistry too. Calling out the reviewers by publishing their names might be of some benefit, although I could see that quickly becoming even more of a quid pro quo environment. High quality publications rely on knowledgeable editors accurately identifying appropriate reviewers, and ensuring the review is thorough and fair. I however don't think that editors can always dedicate the necessary time and intellectual capital to the review process in addition to their "other" job - professor, scientist etc. This is one place where I feel journals could increase staff editors (with advanced degrees and current knowledge) to increase the time a prospective article is vetted. God knows the ACS makes enough cash each year to pick up a few more staff.

I'm also not convinced that every publication gets the right mix of reviewers for each article - there are frequent enough blatant errors in biology, chemistry etc. that ought be caught by even mildly talented reviewers that I don't think every med chem piece goes to a med chemist, a biologist, a pharmacologist (as appropriate). I've not seen any publications recently that are so unique in their science that there isn't at least one other group in the world doing something like it who could vet it.

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22. Will on February 20, 2010 11:56 AM writes...

I wouldn't call this a 'chemist's complaint'.
I'm a biologist in industry and it is basically the first thing I would look at.

The paper is biologically useless- unless a structure is disclosed. I'm not even going to read it until I see a structure.

Also, many biologists can pick out the obvious 'red flags' : size, reactivity, octopus-like, etc...

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23. PharmaHeretic on February 20, 2010 3:04 PM writes...

Speaking of TZDs..

--
Research Ties Diabetes Drug to Heart Woes
By GARDINER HARRIS
Published: February 19, 2010

Hundreds of people taking Avandia, a controversial diabetes medicine, needlessly suffer heart attacks and heart failure each month, according to confidential government reports that recommend the drug be removed from the market.

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24. p on February 20, 2010 9:28 PM writes...

@21: I believe Angewandte employs editors who have that has their primary (or only) job. I, too, think this is a good idea.

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25. Ty on February 21, 2010 3:50 AM writes...

I've long been wondering... what makes these thioamides/thiourea so promiscuous? Most other promiscuous hits fall into either aggregator or electrophile group. What's with this C=S things? What do they do?

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26. GladToMoveToProcess on February 21, 2010 11:10 AM writes...

Agreed that the biologists are the worst, but chemists too sometimes are guilty. I recall a JOC paper by a Big Name (editor of another journal, top-tier school, etc.) 10 or 15 years ago; they used something, specified only by an acryonym (XYZZY, let's say), to make heterocycles I was interested in. Nowhere in the paper did a full name, or the structure, of XYZZY appear. The guts of XYZZY were obvious from the chemistry, but the exact protecting, leaving, and activating groups were anyone's guess. Tried the references (I was between jobs, without online access to journals, and had only my personal copies of JOC and JACS), found two earlier JOC papers, by the same group, using XYZZY, again without the structure. Finally got it via a trip to a (not very close) university library that had the original (Synthesis? TetLett?) paper. Ridiculous!

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27. Pete on February 21, 2010 9:17 PM writes...

If the structure isn't revealed, the work cannot be repeated. It really is that simple and the journals should brief their referees accordingly.

Carmen's point reminds me of another approach that sometimes gets used in talks. I have seen presentations in which claims of activity are 'reinforced' with pretty, colored blobs that represent the molecules. Perhaps the unwholesomeness of the molecules that some of these are hiding could be coded as a scatological shade of brown...

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28. Chris on February 22, 2010 7:12 AM writes...

Perhaps we should insist that all structures are registered in a freely available database, such as ChemSpider? http://www.chemspider.com/

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29. petros on February 22, 2010 8:34 AM writes...

Some chemists aren't so immune from the issue. I sat through lots of early talks from Astex where they only showed fragments or modified fragments before talking about the potency of final compounds.

Some biological journals are better than others. The British Pharmacology Society insists that any talk about a new compound must disclose the structure(s) whose activity is described.

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30. Rosie on February 22, 2010 8:51 AM writes...

Probably a combination of comment 2 (they want to publish an beef up their CVs) and maybe they or their employer (OSU?) or a potential licensee might want to file a patent application.

Many biotech companies won't allow work to be published until after the underlying patent application publishes, or at least is filed.

What they guys are doing might be an attempt to drum up interest (and attracting licensees?) without completely blowing their chances to patent. Just a thought.

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31. jekbradbury on June 19, 2010 9:57 PM writes...

My God - I thought Big D wasn't being serious, then I found that that exact paper does in fact exist... http://www.ncbi.nlm.nih.gov/pubmed/19442136
I also echo Ty's request - what, exactly is the issue with rhodanines?

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32. drsnowboard on September 8, 2011 5:05 AM writes...

@9 http://web.wi.mit.edu/sabatini/pub/publications.html for torin 1, but you've probably made it by now..

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