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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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« More Details on T-Cell Leukemia Therapy | Main | Udo Opperman At The Challenges in Chemical Biology Conference »

July 24, 2013

Stuart Schreiber at the Challenges in Chemical Biology Conference

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Posted by Derek

I'm listening to Stuart Schreiber make his case for diversity-oriented synthesis (DOS) as a way to interrogate biochemistry. I've written about this idea a number of times here, but I'm always glad to hear the pitch right from the source.

Schreiber's team has about 100,000 compounds from DOS now, all of which are searchable at PubChem. He says that they have about 15mg of each of them in the archives, which is a pretty solid collection. They've been trying to maximize the biochemical diversity of their screening (see here and here for examples), and they're also (as noted here) building up a collection of fragments, which he says will be used for high-concentration screening.

He's also updating some efforts with the Gates Foundation to do cell-based antimalarial screening with the DOS compounds. They have 468 compounds that they're now concentrating on, and checking these against resistant strains indicates that some of them may well be working through unusual mechanisms (others, of course, are apparently hitting the known ones). He's showing structures, and they are very DOSsy indeed - macrocycles, spiro rings, chirality all over. But since these assay are done in cells, some large hoops have already been jumped through.

He's also talking about the Broad Institutes efforts to profile small-molecule behavior in numerous tumor cell lines. Here's a new public portal site on this, and there's apparently a paper accepted at Cell on it as well. They have hundreds of cell lines, from all sorts of sources, and are testing those against an "informer set" of small-molecule probes and known drugs. They're trying to make this a collection of very selective compounds, targeting a wide variety of different targets throughout the cell. There are kinase inhibitors, epigenetic compounds, and a long list of known oncology candidates, as well as many other compounds that don't hit obvious cancer targets.

They're finding out a lot of interesting things about target ID with this set. Schreiber says that this work has made him more interested in gene expression profiles than in mutations per se. Here, he says, is an example of what he's talking about. Another example is the recent report of the natural product austocystin, which seems to be activated by CYP metabolism. The Broad platform has identified CYP2J2 as the likely candidate.

There's an awful lot of work on these slides (and an awful lot of funding is apparent, too). I think that the "Cancer Therapeutics Response Portal" mentioned above is well worth checking out - I'll be rooting through it after the meeting.

Comments (23) + TrackBacks (0) | Category: Cancer | Chemical Biology | Infectious Diseases


COMMENTS

1. Hap on July 24, 2013 10:30 AM writes...

Austocystin looks an awful lot like the aflatoxins. I assume it doesn't behave as badly?

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2. Anonymous on July 24, 2013 11:05 AM writes...

Why is Schreiber so famous in the organic chem world?

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3. Anonymous on July 24, 2013 11:28 AM writes...

Why is Schreiber famous at all? How fraction of people walk out with nothing in his lab? Just from what I see of his work it may be quite high.

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4. ESIMS on July 24, 2013 11:33 AM writes...

I have been waiting for a big paper about the small molecule (SM) cancer cell line screen for some time. I really like the approach to hit them with 2 "known" SMs at the same time and try to tease apart what signaling pathways you have to hit to kill a cancer with a particular genetic background (SM based synthetic lethality screen).

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5. Anonymous on July 24, 2013 11:38 AM writes...

is he creating a small molecule bubble or universe?

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6. carlos danger on July 24, 2013 11:40 AM writes...

Hi Derek,

The first link you have provided about increasing the diversity of compounds screened isn't working.

Thanks,

Carlos

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7. Anonymous on July 24, 2013 12:06 PM writes...

2+3: This has been around a while, unproductively: see http://pipeline.corante.com/archives/2010/09/28/nobel_season_2010.php
From that thread:

24 (Amadeus): Has Schreiber produced one decent student or postdoc that has gone on to become a good and productive faculty member? I cannot think of any at the moment....

25 (Donna) Amadeus: Mark Albers, Derek Tan, Laura Kiessling, Tim Jamison, to name a few of his former grad students.

26 (Sammy) Amadeus, include Amir Hoveyda, John Porco, James Chen, Michael Rosen, Tarek Sammakia, Jack Taunton, Brent Stockwell, Greg Weiss, Randy Peterson, Tom Wandless...

There's an awful lot of hype around Schreiber's stuff, but that seems like a pretty good list of grads/postodcs, no?

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8. Anon on July 24, 2013 12:52 PM writes...

Ah, cue the predictable Schreiber-bashers. Do you know how many of his students occupy respectable positions in academia and industry? If nothing else he would be quite famous as a great trainer of scientists. And if nothing else his philosophical impact on the field has been enormous; before him the whole field of using small molecules to interrogate biological systems was a backwater. In any case, those who point the way forward know they aren't in a popularity contest, so it's ok.

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9. Derek Lowe on July 24, 2013 1:26 PM writes...

#6 Carlos - fixed! Thanks. . .

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10. paperclip on July 24, 2013 1:58 PM writes...

@1 Yeppers, not only does austocystin look like the aflatoxins, they are probably biosynthetically realted. But there are glimmers of hope that austocystin would be selective for cancer cells.

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11. NMH on July 24, 2013 2:05 PM writes...

Ah yes, cue the predictable Schreiber-acolyte (is he reviewing your grant?)

" Do you know how many of his students occupy respectable positions in academia and industry?"

Great. A lot of people trained exactly the same way, doing similar things. Is this good for academia or industry?

"If nothing else he would be quite famous as a great trainer of scientists."

Is he training anybody or are his grad students/post-docs figuring things out by themselves through trial and error, while he takes the best ideas from his post-docs and writes them up for grants?

" And if nothing else his philosophical impact on the field has been enormous; before him the whole field of using small molecules to interrogate biological systems was a backwater."

Maybe its a backwater because others have determined its not worth a lot of time and money, but his name is SS at Harvard so he'll get funding anyway.

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12. Buyandbye on July 24, 2013 2:08 PM writes...

Carlos Danger... Lmao!

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13. Anon on July 24, 2013 2:17 PM writes...

How predictable. Don't like what someone says about your favorite punching bag? Tar them as acolytes/sycophants. Please, I have never met Schreiber, never met any of his students and never had anything to do with him. But I am quite familiar with his work, and while it's often hyped (mainly by others), anyone who says that he has made no notable contributions to chemistry and biology is simply ignorant of scientific history.

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14. Anonymous on July 24, 2013 2:23 PM writes...

Others were doing "chemical biology" before Schreiber. There are even indications in old notebooks that Woodward was so inclined but died too soon to make the shift. Glenn Prestwich was doing chemistry AND biology and biochemistry about 10 or more years before Schreiber but remained focused on specific systems.

One thing is for sure: good ideas aren't enough; you have to be able to sell those ideas to the money-men to have a chance to realize them.

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15. MoMo on July 24, 2013 2:51 PM writes...

Its not that Schreiber is erroneous or malfeasant at chemistry, as an American he can follow the dream and at one time I throughly enjoyed reading his articles- its just that its all we ever hear about and is funded- Schreiber! Schreiber said this, Schreiber said that! Blah! Blah! Blah!

He's becoming the Barbara Streisand of chemistry- he won't get off the stage and is making the younger generation nauseous!

And, like Barbara, he pulls in the big ticket prices from the geriatrics!

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16. Curious Wavefunction on July 24, 2013 3:12 PM writes...

But does he really still get so much publicity? Although he is still undoubtedly prominent, I rarely hear of him being touted these days as the chemical biology community's leading champion; that title seems to have passed on to young stars like Jason Chin, Wendell Lim and Jay Keasling, people who are doing things like fluorescent protein tracking, synthetic biology and nonstandard genetic codes. Schreiber's work is certainly considered important (and I tend to agree) but I think people seem to have moved on. In fact most of the spirited discussion about his work seems to come not from the mainstream research community but from his critics and supporters on forums like this one.

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17. Andy on July 24, 2013 3:16 PM writes...

Interestingly, the 3 other scientists mentioned by Curious Wavefunction have primary appointments in departments other than chemistry.

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18. anchor on July 24, 2013 3:52 PM writes...

@ 7 - the name Schreiber is like a name brand! If you can afford me and my style, you can work for me and are welcome! Everyone who wears Armani does not become famous!

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19. Chubbant on July 25, 2013 4:30 AM writes...

@ 5 - what is the definition of a 'universe'? Would 28 million count? FWIW, we put together 28m combinatorial compounds, the core of which can be synthesized... so in theory all should be chemically feasible. Sadly no stocks available, so it's just theoretical. Methods in the paper.
http://pubs.acs.org/doi/abs/10.1021/ci100443x
http://chemware.ucd.ie/webtest/chemware/login.php

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20. Anonymous on July 25, 2013 9:21 PM writes...

That darn DOS libraries... Awful lot of them contain copper (think click)... Makes them appear awfully active in some assays... Maybe in the cell, too? Who knows?

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21. A non-Amos on July 28, 2013 2:24 PM writes...

#20 - as opposed to most libraries that rely on transition metal couplings? There are trace metals in most collections (Derek blogged on this a while back). I doubt DOS is any better/worse. Besides, standard follow-up chemistry and assays will tell you whether a hit is actually a false positive.

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22. LeProf_7272 on August 15, 2013 8:13 PM writes...

I am neither basher nor acolyte. I have enjoyed stimulating talks from/with Professor S, and cordial, productive relations with his lieutenants, while remaining critical of over-crediting fundamental insights in a field whose origins date to the late 19th century, and whose practices and concepts originated and continue to overlap with various other interdependent, sophisticated disciplines.

Having said this, I would offer the following comments, related to the foregoing discussion, or nearly so:

(1) Comments that are anonymous, and personal or approaching so, and pejorative, relating to living, contributing academic or industrial individuals in the sciences, can, Derek, in my view, be eliminated at this site. Your call, sir, but I for one will not miss the noise.

(2) One need not diminish others and other disciplines, to recognize the seminal contributions of Schreiber and his group. The notion that chemical biology was created de novo, and that the interrogation of biological systems was a backwater theretofore **is utter rubbish**, and an insult to the thousands in pharma and academic discovery scientists that used synthetic affinity technologies, small molecule series design, structure-based design, and traditional medicinal chemistry successfully, repeatedly with great societal impact, long before CB was defined and popularized. We all see far because we all stand on the shoulders of giants.

(3) That the property and structure space occupied by natural product fragments with higher than mean/median stereochemical "richness" is distinct from the property space occupied by more druglike fragments (Tan's review work, e.g., Bauer et al, COCB 2010) is fundamentally sound, rooted in good chemistry, pharmacology, cheminformatic and pharma experience, and will be revolutionary once its implications, small and large, find their way into discovery workflows. That the aims of Broad program-supported DOS builds on this insight will provide a slow, grinding, but critically important set of contributions, esp. critical as pharma chemists and early discovery programs are such slow adopters of bold new conceptual platforms. (My pharma alma mater, one of the first with an agent targeting ptn-ptn interactions, a decade before in-house declared the idea infeasible, alongside nixing a proposal to investigate the possibility of selective kinase inhibition.)

(4) My interactions with senior Broad scientists have proven them to be strongly wed to hypothesis-driven approaches and to thorough programs of study of deeper questions (vs quick one offs), providing an enlightening set of interactions to this OChemist used to something of a norm of purely post-hoc rationalizations of mechanism.

(5) Finally, there is a great need for professionals with enough time to make electronic contributions of various sorts to have a look at chemistry offerings in wikipedia. I edit there, and am not a big fan, but there is no gainsaying its reach and impact. I have complained twice about the status the chemical biology page, there. Perhaps some listeners, here, would have time to make that article as substantial as the learning of this august group on this subject.

With the exception to all except the anonymous, kudos for thoughtful comments and, as always, to Derek for the hard work of maintaining an important site for pharma and academic discovery intel.

Cheers, LeProf

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23. NYChemist on October 22, 2013 5:23 AM writes...

Well said, LeProf

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