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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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March 30, 2012

Ciliobrevins: Digging Into Cell Biology

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Posted by Derek

Back in 2009 I wrote about a paper that found a number of small (and ugly) molecules which affected the Hedgehog signaling pathway. At the time, I asked if anyone had done any selectivity studies with them, or looked for any SAR around them, because they didn't look very promising to me.

I'm glad to report that there's a follow-up from the same lab, and it's a good one. They've spent the last two years chasing these things down, and it appears that one series (the HPI-4 compound in that first link, which is open-access) really does have a specific molecular target (dynein).

There are a number of good experiments in the paper showing how they narrowed that down, and the whole thing is a good example of just how granular cellular biology can get: this pathway out of thousands, that particular part of the process, which turns out to be this protein because of the way it interacts in defined ways with a dozen others, and moreover, this particular binding site on that one protein. It's worth reading to see how they chased all this down, but I'll take you right to the ending and say that it's the ATP-binding site on dynein that looks like the target.

Collectively, these results indicate that ciliobrevins are specific, reversible inhibitors of disparate cytoplasmic dynein-dependent processes. Ciliobrevins do not perturb cellular mechanisms that are independent of dynein function, including actin cytoskeleton organization and the mitogen-activated protein kinase and phosphoinositol-3-kinase signalling pathways. . .The compounds do not broadly target members of the AAA+ ATPase family either, as they have no effect on p97-dependent degradation of endoplasmic-reticulum-associated proteins or Mcm2–7-mediated DNA unwinding. . .Our studies establish ciliobrevins as the first small molecules known specifically to inhibit cytoplasmic dynein in vitro and in live cells.

So congratulations to everyone involved, at Stanford, Rockefeller, and Northwestern. These ciliobrevins are perfect examples of tool compounds. This is how academic science is supposed to work, and now we can perhaps learn things about dynein that no one has been able to learn yet, and that will be knowledge that no one can take away once we've learned it.

Comments (15) + TrackBacks (0) | Category: Biological News


1. lynn on March 30, 2012 8:26 AM writes...

Yes - really good work. Figuring out true targets is important and not often as well done. But I have a naive biologist's question. Why do you call these ugly molecules?

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2. Dr. Z on March 30, 2012 8:32 AM writes...

Is it my browser or your italics "key" that's broken?

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3. Rick Wobbe on March 30, 2012 8:39 AM writes...

Maybe I'm just slow or cranky this morning and this is part of your point, Derek, but it also gives an idea of the kind of strides drug discovery could have made had it been less dogmatic about a particular, linear pathway of target validation and mechanism of action in the official "Drug Discovery Process". For example, it illustrates how tools of target validation can be used, with even more enlightening results, for target elucidation and lead optimization as follow up to a less target-dogmatic screening process. In an orthodox drug discovery organization, these guys would have been laid off years ago for "producing nothing".

And you know what? This type of research happens all the time. Lately, it's been dubbed chemical biology or chemical genetics or molecular pharmacology or pharmacologic target validation. Independent of the trendy names we give it, it's just what cell biologists and biochemists have done for centuries.

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4. chrisL on March 30, 2012 11:54 AM writes...

An analog of HPI-4 with the exact same scaffold but without the two chlorines (CAS 302803-65-2) is active in an antimalarial HTS screen. I have no idea what this means biologically but it is consistent with the idea that poly-pharmacology is the rule rather than the exception for lots of compounds.
(Pillai, Ajay D.; Pain, Margaret; Solomon, Tsione; Bokhari, Abdullah A. B.; Desai, Sanjay A. A cell-based high-throughput screen validates the plasmodial surface anion channel as an antimalarial target. Molecular Pharmacology (2010), 77(5), 724-733.)

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5. processchemist on March 30, 2012 12:14 PM writes...


The central part of HPI-4 reminds me of teriflunomide, and I remember some DOD inhibitors proposed as antimalarials.... No tests for cell viability or P53 activation in the PNAS paper so who knows?

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6. Cellbio on March 30, 2012 12:53 PM writes...

Just looked at the first paper they published, and the curve shape of HPI-4 in the Hh pathway assay is pretty ugly (cell biologists equivalent to ugly molecule). Activity rises to nearly 150% of control before dropping off a ledge. Either really strange binding mechanism to a single target, or polypharmacy or membrane pickling. I worry about mucking up membranes in Hh signaling assays. Personally, I wouldn't bet on a compound with such a curve shape at 10 uM, but that is just my opinion from doing primary cell screens and seeing this phenomenon so many times that we had to rule it out as we could not weed through the artifacts to try to find out if any compound was doing anything by a drug-like mechanism.

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7. Anonymous on March 30, 2012 3:20 PM writes...

"...and that will be knowledge that no one can take away once we've learned it": that wasn't the lesson of the Dark Ages.

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8. dearieme on March 30, 2012 3:20 PM writes...

"...and that will be knowledge that no one can take away once we've learned it": that wasn't the lesson of the Dark Ages.

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9. No one else mentioned? on March 31, 2012 12:44 AM writes...

Colloidal aggregators?

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10. Anonymous on March 31, 2012 2:02 PM writes...

If you look at Supplementary Fig. 14, HPI-4 has an IC50 of 50 uM against purified dynein. In the next figure, the authors use the compound in vitro at 150 uM. This paper is a joke.

Agree with Cellbio about the strange dose response curves as well. Not to mention the absurd electrophilic scaffold that resembles an anti-malarial.

I'm sort of surprised that this kind of stuff can still get published in Nature. In my experience, 100 micromolar compounds are basically never useful as "tools" or "probes for biology". They're just a waste of everyone's time.

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11. Cellbio on April 1, 2012 12:54 PM writes...


i too am amazed to see this in a Nature journal, but read it as an example of current "chemical biology" that traverses a set of data at high altitude, weaving together a story that appears to come to completion, but that story is merely consistent with one interpretation of the data, with one eyed closed and squinting, and hardly rules out a host of other explanations. At the concentrations used, they are almost approaching the respectable concentration of salt. Problematic in enzyme assays, foolish to read biological effects. I remain skeptical unless you show me the several thousands of things that you did not measure are operating without interference. At what concentration would formaldehyde appear active, or a cholesterol derivative that would alter membrane fluidity? I also wonder if there would be dose response with these agents in regard to certain pathways being the first to go off.

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12. Anonymous on April 1, 2012 5:06 PM writes...

It's disappointing that the authors didn't do much med chem to improve the affinity and generate more reasonable compounds. That would actually have been valuable. Given that Kapoor and Chen are chemists, you'd think that would be the first thing they'd do. My guess is that they tried and found that these structures are a dead-end.

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13. Anonymous on April 2, 2012 6:03 AM writes...

It's ridiculous! Just add enough Mercaptoethanol and Glutathion to any counter assay where you do not want to see activity and leave it away if you want to see activity. Voila, "favourable selectivity profile". The reason: THese are reactive monsters that inhibit anything. It's just a matter of intercepting these warheads appropriately by specific assay conbdition.
We all know that and these phenomena occurr on a dayly basis in HTS. Nothing to do with anything valuable!

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14. jD on April 2, 2012 3:49 PM writes...

Am I missing something? What about the original structures warrants the label of 'ugly'?

Regardless of the biology, I just don't see what the big issue is. The chemical structure ideology at play here is really getting out of hand. If I had identified any of those hits in my screens, I'd be perfectly happy with them. Ideal? Perhaps not. But ugly???

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15. anon on April 4, 2012 7:04 PM writes...

some of the concerns are legitimate, but the compound has negligible electrophilicity.

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