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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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« A Response From Sanofi | Main | Department of Lots of Nerve (Patent Applications Desk) »

March 5, 2012

Trouble With a Boron-Containing Drug Candidate

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Posted by Derek

There have been all kinds of boronic acid-based enzyme inhibitors over the years, but they've been mostly locked in the spacious closet labeled "tool compounds". That's as opposed to drugs. After all these years, Velcade is still the only marketed boron-containing drug that I know of.

There's been a good attempt to change that in antibacterials, with the development of what's commonly referred to as "GSK '052", short for GSK2251052. That's a compound that originally came from Anacor about ten years ago, then was picked up by GlaxoSmithKline, and it's an oxaborole heterocycle that inhibits leucyl tRNA synthetase. (Here's a review on that whole idea, if you're interested).
Unfortunately, last month came word that the Phase II trial of the drug had been suspended. All that anyone's saying is that there's a "microbiological finding", which isn't too informative when it's applied to y'know, an antibacterial trial. (At least it doesn't sound like a general safety or tox problem, at any rate).

Anacor is continuing to exploit boron-containing compounds, although opinion looks divided about their prospects. I always have a sneaking fondness for odd compounds and elements, though, so I'd have to root for them just on that basis.

Comments (19) + TrackBacks (0) | Category: Infectious Diseases | Odd Elements in Drugs


1. canchem on March 5, 2012 8:58 AM writes...

I had put forward a boron-containing candidate for an antibacterial program a couple of years ago. The higher-ups were suspicious, to say the least, but it was a single step synthesis from a stockpiled intermediate, so they let me try it out. Bugger had no activity... Oh well, c'est la vie.

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2. Curious Wavefunction on March 5, 2012 9:17 AM writes...

"Microbiological finding"? The bugs mopping it up and feeling even more energized? Or chopping it up and discarding it like last night's leftovers?

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3. SP on March 5, 2012 9:21 AM writes...

Maybe they started incorporating it into their DNA.

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4. eugene on March 5, 2012 9:24 AM writes...

Boron salts play a role in signalling between different bacteria (quorum sensing), so I could see it as playing a positive signalling role for some certain species. Maybe promoting the creation of a biofilm.

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5. anon2 on March 5, 2012 9:30 AM writes...

Like any individual development candidate in Phases 1 or 2, this compound was always a long-shot to be a successfully demonstrated effective & safe drug. And more to the point, how many new chemical classes have been approved for use by FDA in the past 20 years as an oral antibacterial? Not a good track record.

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6. monoceros4 on March 5, 2012 10:38 AM writes...

"After all these years, Velcade is still the only marketed boron-containing drug that I know of."

Doesn't boric acid count? (I know, I know.)

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7. luysii on March 5, 2012 11:40 AM writes...

I wouldn't call AL-2 a salt, but it is used as a quorum sensor by a wide variety of bacteria. It starts out innocently enough as 2 hydroxy, 3 keto 4 keto 1 pentanol, but then forms a bicyclic ketal containing a boron ester. For the structure see Nature vol. 415 p. 546 '02.

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8. KW's hairdresser on March 5, 2012 11:51 AM writes...


Zhi Hong, who directs GSK's Infectious Disease unit, fired nearly the entire chemistry staff in the states a year ago ostentibly to provide funds for GSK '052's development whilst touting this
"breakthough" molecule. Ironic.

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9. Kyle on March 5, 2012 12:55 PM writes...

Not knowing anything about the drug industry, why exactly is boron specifically avoided?

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10. Anonymous on March 5, 2012 1:26 PM writes...

It sounds like there was resistance seen with the compound during therapy [3 of 30 patients had what sounds like post-therapy raised MICs]. Not really unexpected with an inhibitor of a single enzyme If they can go up in dosage, they may be able to retard resistance development.

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11. partial agonist on March 5, 2012 1:27 PM writes...


It has more to do with the issue of covalent target modification. When you see a boron, it is likely there to interact covalently with a suitably place biological nucleophile, such as a serine side chain.

Many pharma companies have a strong bias against covalantly-acting compounds for anything but acute therapy, for several reasons not explained well in a quick blog post. Quick synopsis: there are concerns with target specificity and with potential immune responses to a modified protein (that's not as much a concern when the interaction is covalent but reversible,as is the case here, however)

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12. gippgig on March 5, 2012 2:31 PM writes...

Boron has an unusual ability to exist in both 3-coordinate (B(OH)3) and 4-coordinate (B(OH)4-) complexes (including simultaneously in the same molecule (see borax)). This gives it a very complex chemistry that should have unique uses. This has nothing to do with drugs, but I'm intrigued by the possibility of it acting as an ion channel - consider a channel blocked by RRBOH. OH- could bind to the B from one side, then the OH originally attached to the B could be released from the other side. It would be a molecular turnstile. Anyone have any idea if anybody has considered this?

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13. Anonymous on March 5, 2012 5:55 PM writes...

Keep in mind that it was this molecule that was used by senior management at GSK (in public interviews) to justify them ignoring the recommendations from GSK scientists to also not invest in Sirtris when questioned in the press about all the science that turned out to be faulty. I forget which one (Vallance, Slaoui or Witty) but they said that their internal scientists also didn't want them to invest in this company (Anacor) either. They ignored their internal scientists in both cases. Fortunately, theirs no accountability in management so they can fail every time and still rake in the millions. Unbelievable.........

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14. Anonymous on March 5, 2012 8:12 PM writes...

sorry, it's 'there's no accountability'........sorry for the typo........

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15. noname on March 5, 2012 8:27 PM writes...

Boronic acids readily form boronate esters with the 1,2- and 1,3-diols of saccharides, such as those that coat the surface of mammalian cells..........

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16. luysii on March 5, 2012 10:04 PM writes...

Just wondering if anyone out there managed to figure out the actual structure of AL-2 just from the description I gave, without looking up the reference. If you haven't, give it a shot. #15 noname gives a useful clue

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17. eugene on March 6, 2012 6:12 AM writes...

luysii, AI-2 (not AL) is formed by the reaction of an organic molecule with a boronic salt, which does not necessarily invalidate my comment. Incidentally, the starting molecule is a good substrate to try for a current project, but I don't think I'll have time before we send out the publication.

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18. bosshogg on March 6, 2012 7:49 PM writes...

Damn...I still have a suitcase full of Boron elixirs to unload. Uh, step right up and get your deuterated-antimicrobial pills...

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19. anon2 on March 7, 2012 12:55 PM writes...

18, bosshogg:
Try selling your deuterated ""whatever for"" little pills to Concert.....

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