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March 30, 2012
Ciliobrevins: Digging Into Cell Biology
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.
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