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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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October 12, 2012

Controversial Scaffold Is Right

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Posted by Derek

Let's talk tool compounds. This topic has come up around here before, generally when some paper gets published from an academic group featuring a hideous molecule. Today, alas, is no exception. Feast your eyes on this one, an inhibitor of tyrosyl-DNA phosphodiesterase I.
Now, on one level, I'm sympathetic. That's an unusual enzyme, and there really aren't any decent inhibitors known for it. It's pretty hard to work out the function of an enzyme without a good inhibitor to watch the effects in living cells, and in that sense, it's good to have found something. But here comes the other hand: your compound for such a purpose needs to be a good one, or the studies you run with it risk being meaningless. "Good" is a relative term, I realize, depending on how much you're expecting the compound to do for you: enzyme assay only? Cells? Mice? But at a minimum, it should be selective for the target you're trying to figure out.

And that's where my eyebrows go up with this little beast. It's not quite a rhodanine (switch the carbonyl and thiocarbonyl if you want that), but it's not a particularly pretty heterocycle, either. This paper, which I wrote about here, looked at the promiscuity of several related heterocycles, but not this one in particular. Any time I see a thioamide group, I get worried. This very system, in fact, shows up in the PAINS paper (open access copy), which I blogged about here, warns against this whole class (see page S45 of the supplementary material).

It also warns, with good reason, against the alkylidene branching off of such rings. I know that there are drugs with such features (epalrestat, Sutent), but your chances of such compounds being real and going all the way are surely lower. Finally, we come to the triphenol. Polyphenol compounds are notorious in medicinal chemistry. They're reactive, they're unstable, they show up in all kinds of assays, and their SAR almost never makes any sense. So this compound has lots going for it.

The authors realize this, and checked the compounds against bovine serum albumin as a way to assay nonspecific protein binding. They also did some work with whole-cell extracts, and continue to feel that these "controversial scaffolds" (their words) can still be useful. (And to be fair, they're also looking at replacing the phenolic section with less nasty polar groups). But while their hearts (and their heads) are in the right place, I still worry very much about these compounds. I'd be quite interested in seeing them run across a broad panel of assays, just to see how promiscuous they really are, and I would be very careful about trusting cellular data (or anything close to it) until that's done.

Comments (24) + TrackBacks (0) | Category: Drug Assays


1. myma on October 12, 2012 8:53 AM writes...

On a plus side, I bet this thing has potential for interesting photochemistry like maybe that neato quantum box thing.

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2. JAB on October 12, 2012 8:54 AM writes...

Gotta agree with your doubts. We've worked with the Pommier group on this target, as did the NIH Roadmap gang, and not much has come out of the search for Tdp1 inhibitors despite an awful lot of screening, in both synthetic libraries and natural products extracts. Perhaps fragment based screening will crack this one?

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3. ScientistSailor on October 12, 2012 9:11 AM writes...

I saw that abstract and thought it was an early (or late) April fools joke.

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4. anon the II on October 12, 2012 9:16 AM writes...

Their hearts may be in the right place, but their heads are definitely not. This is a bad compound. It shouldn't be in a screening collection of any research group other than one looking a new glues.

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5. MikeyMedChem on October 12, 2012 10:12 AM writes...

there's another beaut of an HTS Hit recently published: DOI: 10.1021/jm300789g.

Polyphenols and rhodanine-reminiscent scaffolds give me the willies. Pretty sure that that hit would not have made it past the visual compound filter (unless that was the BEST of the hit matter!)

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6. Hap on October 12, 2012 10:17 AM writes...

o-Hydroxystyrenes are potentially isomerizable to the quinone methides (via 1,5-H shift), which would likely be pretty nonspecific and would bind covalently to whatever's around. There was a paper (recently - 2011 or 2012) which described the generation of a cannabinoid-type skeleton by isomerization of an alkenyl vinylphenol followed by intramolecular Diels-Alder with the quinone methide. This substrate is electronically different, but it's still another possible problem.

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7. nine on October 12, 2012 10:19 AM writes...

Hi Derek, TIFF images don't work so well in Chrome on Mac, could you replace with a PNG version? Here's a converted copy:

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8. milkshake on October 12, 2012 10:23 AM writes...

nice tannin-rhodanine hybrid. It is destined to interact with proteins - with all of them.

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9. partial agonist on October 12, 2012 10:42 AM writes...

As an academic who searches for tool compounds on a regular basis, this is an abomination.

If it appeared on one of my lists of "screening hits" I would red-flag it as "non-tractable, likely an artifact" and move on. If there were no other hits, I would sum up the screen as "gave no useful hits".

The biologists may complain, since they might point to a very pretty curve, and to them most likely the compound is just a number rather than a structure, but you've got to be intellectually honest.

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10. partial agonist on October 12, 2012 10:58 AM writes...

it's also a quinone. Move the proton from the para OH to the S of the thiocarbonyl.

Thus it is an
-electrophilic and perhaps a Michael acceptor,
-it likely would be rendered useless with any glutathione around,
-as a polyphenol it probably is prone to self-aggregation,
-it is certainly promiscuous- you can't convince me this won't bind in 15% of screens, whatever the target
-it's probably not even very soluble

how many strikes is that?

Maybe they could stick on a nitro group and an ester or two to set some kind of record!

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11. gippgig on October 12, 2012 2:56 PM writes...

Approximately what fraction of the ~20000 (well, I'm ignoring splicing variants which I admit is just plain wrong) human proteins have good tool inhibitors?
It would be interesting and probably quite useful (for research) to test the effects of specific inhibitors of each protein on the transcriptome. Testing all pairs (yes, that's a HUGE number) and noting which ones have nonadditive effects should be a good way of identifying interacting proteins/pathways. Anyone trying this?

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12. Anonymous on October 12, 2012 3:09 PM writes...

Does anyone have any literature on the issues with polyphenol scaffolds and why they are poor drug candidates? We recently got an HTS hit that contains an ortho and para hydroxyl on a phenyl ring and it is giving us some odd SAR results...

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13. B on October 12, 2012 3:26 PM writes...

@11: Here is an interesting article on drugging the proteome, not so easy as one might think.

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14. You're surprised? on October 12, 2012 7:53 PM writes...

Typical academic garbage. Since it's from the University of Minnesota, I'm sure the editorial staff from J. Med. Chem. accepted without revisions. A truly delusional department and program.

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15. Jose on October 12, 2012 11:04 PM writes...

re: #14, it feels unfair to chuck all academic med chem into the garbage pile, but seriously, the more papers like this I see the more I feel inclined. That compound is simply a joke, and trying to defend it in JMedChem makes the massive divide even more humorously apparent.

It reminds me when EC skiers try and convince you how much better the skiing is than out West. Just by trying to assert that, it's obvious they have not the slightest clue what they are talking about.

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16. Anonymous on October 13, 2012 11:59 AM writes...

hey morons, that work is not from the med chem dept at Minnesota...look again little monkey and "you're surprise" will be how stupid you are....

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17. defendingtheundruggable on October 13, 2012 1:57 PM writes...

#14/15, Take a look at figure 2, "Known inhibitors of Tdp1", and weep. It's academic research that's going to save the pharma industry, didn't you know that...?

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18. hoo boy on October 13, 2012 9:54 PM writes...

The Center for Drug Design? Is this what their designers come up with? God help us all.

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19. Curt F. on October 17, 2012 5:35 AM writes...

The abstract of the paper contains statements that no one here is challenging. The authors found an inhibitor to an understudied enzyme. They characterized it. Why on Earth is it inappropriate for them to publish their findings?

If the complaint is that this work never should have been done, where were all the naysayers when the grant that funded this work was awarded? Publications should be evaluated on the soundness of the data and the quality of the experimental work. It's too late to criticize publications for working on the wrong topic -- the money has already been spent. The attitude that this molecule isn't good enough raises the bar on what is publishable that simply isn't justified.

If the complaint is that someone out there has better inhibitors for this enzyme, then either publish a paper or provide a link to a paper.

If the complaint is that this molecule raises too many red flags to be useful to the "working medicinal chemist", that's fine -- then don't use this molecule. I'm not sure why it's so horrible for a group to have worked on it briefly and then published their results. Do folks have an attitude that J Med Chem should publish only papers that are personally and directly useful to the project that they are currently working on? That is almost comically short-sighted.

Am I missing some other basis for complaint about this paper? In my view, this paper presents sound science and thus represents a (very small) increase in the world's total knowledge of biochemistry and medicinal chemistry. From where I sit most of the criticisms so far sound almost hostile to the idea of presenting this new knowledge to the world. On what is usually a very pro-science, pro-chemistry blog, it is honestly a bit saddening to see.

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20. Anonymous on October 17, 2012 9:37 AM writes...

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21. defendingtheundruggable on October 17, 2012 1:58 PM writes...

@19, what you are missing is summed up quite well here:

This is NOT an argument about "drug likeness". Most researchers genuinely don't know how to remove false positives from their screening results. A few classes of compound keep turning up in the literature as hits against every target under the sun.

If success is measured by publication count, there's no incentive to do more work to check that hits are kosher. Just publish it quick, add another line to your CV, and move on.

So what? Well, for one thing, a lot of biologists are right now wasting time and money following up dud screening hits that should never have been published.

For another, people with authority to make decisions about people's jobs are unlikely to be able to distinguish between scientists who know how to validate a hit and ones who don't. If I sound angry about this, it's because I know too many good researchers who've been laid off to fund more "innovative" work elsewhere.

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22. Curt F. on October 17, 2012 4:04 PM writes...

@21 defendingtheundruggable --

Thanks for the response. I'm not sure what you mean by "kosher" or by "false positive". Are you saying that their compound does not actually bind to Tdp1? That their compounds bind to Tdp1 seems to be all they are claiming in the paper. Are you sure that the papers' authors would have the same definition of "false positive" and/or "kosher" as you?

Essentially I worry that you want these authors to filter their own work using your own personal definitions of "important" and/or "kosher". Even if your own personal definitions have widespread support among drug developers, it's not clear that it is the only "right" definition.

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23. HTSguy on October 17, 2012 6:09 PM writes...

@22 Curt F.

So what exactly is the evidence that the compounds bind to Tdp1?

Not the SPR data. The experiment shown in the paper is that of a classical high stoichiometry inhibitor. Note the large jump in binding at 50 uM and that even this unsaturated curve hits 100RU, which is greater than the theoretical maximum.

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24. Curt F. on October 17, 2012 6:50 PM writes...

@23 HTSguy.

1. The compound(s) inhibits Tdp1 activity. See figure 5.
2. The compound doesn't bind to the substrate. See figure 6B.
3. The compound gives a concentration dependent SPR signal on immobilized Tdp1, as shown in Figure 6a.

I'm not sure how 1 - 3 could all be true without the compound binding to Tdp1. What mechanism do you propose?

As an aside, I agree that lots more characterization -- along the lines of what Derek mentioned in his final paragraph, would be highly informative. But that doesn't mean that this paper shouldn't have been published without them, at least not to me.

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