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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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November 1, 2013

Just Build The Thing

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Posted by Derek

Here's a paper that's just come out in JACS that's worth a look on more than one level. It describes a way to image prostate cancers in vivo by targeting the GPR receptors on the cell surfaces, which are overexpressed in these tumors. Now, this is already done, using radiolabeled bombesin peptides as ligands, but this new work brings a new dimension to the idea.
What the authors have done is targeted the cell surface with antagonists and agonists at the same time, by hooking these onto a defined molecular framework. That's poly-proline, which is both soluble and adopts a well-defined structure once it's in solution. The bombesin derivatives are attached via a click Huisgen triazole linkage, and since you can slot in an azidoproline wherever you want, this lets you vary the distance between the two peptides up and down the scale. The hope is that having both kinds of ligand going at the same time might combine their separate advantages (binding potency and uptake into the cells).

And that idea seems to work: one of the combinations (the one with about a 20A spacing between the two ligands) works noticeably better than either radiolabeled peptide alone, with greater uptake and longer half-life. I'd say that proof of concept has been achieved, and the authors are planning to extend the idea to other known cell-surface-binding oncology ligands used diagnostically and/or therapeutically. Each of these will have to be worked out empirically, since there's no way of knowing what sort of spacing will be needed, of course.

That's the second thing I wanted to emphasize about this paper. Note how quickly I ran through its basic concepts above - I hope it was intelligible, but I think that the idea (which seems well worth exploring) can be expressed pretty easily. What's striking is how quickly these sorts of things can be realized these days. We've learned more about appropriate scaffolds (one of the authors of this paper, Helma Wennemers, has put in a good amount of work on the polyproline idea). And thanks to the near-universal applicability of the "click" triazole reaction, one can assemble hybrid structures like this with a high chance of success. That's not something to take for granted - doing bespoke chemistry every time on such molecules is no fun. You find yourself getting bogged down in the details rather than getting a chance to see if the main idea is worth anything or not.

There was talk before this last Nobel season of Barry Sharpless getting a second prize for the click work. Some have said that this doesn't make sense, because the click reaction that's been used the most (azide/acetylene cycloaddition) was certainly not a new one. But did anyone else see its possibilities, or the possibilities of any such universal connector reactions? Both providing such reactions and publicizing what could be done with them have been Sharpless's contributions, and the impossible-to-keep-up-with literature using them is testimony to how much was waiting to be exploited. So how come nobody did?

Comments (6) + TrackBacks (0) | Category: Cancer | Chemical Biology


1. gippgig on November 1, 2013 3:03 PM writes...

Did they compare agonist-antagonist with agonist-agonist and antagonist-antagonist?

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2. PorkPieHat on November 1, 2013 7:39 PM writes...

I remember when Sharpless came to our Pfarmaceutical company to give one of his early Click talks there over 15 years ago, there was so much quiet giggling going on. And now...look where he and his Click chemistry are, and look at where the Pfamous Pfarmaceutical Pfactory is now. I can hear him singin' "How ya like me nowww?"

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3. PharmaHeretic on November 1, 2013 8:56 PM writes...

Any comments? Is ARIAD screwed beyond repair?

Doctors Fear Losing Leukemia Drug Deemed Risk

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4. Anonymous on November 2, 2013 4:02 AM writes...

For PET this is next to useless,
it may make some sense for therapy, though most of Maeckes peptides have critical organ issues.

Are the azides actually pointing in the same direction at 10 and 30 Å distance? Whats the torsion to length ratio for polyproline?

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5. anchor on November 2, 2013 7:13 PM writes...

@ 4- I fully concur with you as I am working in a PET area. Greta research but no commercial potential.

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6. anonymous on November 4, 2013 7:02 AM writes...

Please educate - why next to useless for PET?

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