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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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July 18, 2014

Thalidomide, Bound to Its Target

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Posted by Derek

There's a new report in the literature on the mechanism of thalidomide, so I thought I'd spend some time talking about the compound. Just mentioning the name to anyone familiar with its history is enough to bring on a shiver. The compound, administered as a sedative/morning sickness remedy to pregnant women in the 1950s and early 1960s, famously brought on a wave of severe birth defects. There's a lot of confusion about this event in the popular literature, though - some people don't even realize that the drug was never approved in the US, although this was a famous save by the (then much smaller) FDA and especially by Frances Oldham Kelsey. And even those who know a good amount about the case can be confused by the toxicology, because it's confusing: no phenotype in rats, but big reproductive tox trouble in mice and rabbits (and humans, of course). And as I mentioned here, the compound is often used as an example of the far different effects of different enantiomers. But practically speaking, that's not the case: thalidomide has a very easily racemized chiral center, which gets scrambled in vivo. It doesn't matter if you take the racemate or a pure enantiomer; you're going to get both of the isomers once it's in circulation.

The compound's horrific effects led to a great deal of research on its mechanism. Along the way, thalidomide itself was found to be useful in the treatment of leprosy, and in recent years it's been approved for use in multiple myeloma and other cancers. (This led to an unusual lawsuit claiming credit for the idea). It's a potent anti-angiogenic compound, among other things, although the precise mechanism is still a matter for debate - in vivo, the compound has effects on a number of wide-ranging growth factors (and these were long thought to be the mechanism underlying its effects on embryos). Those embryonic effects complicate the drug's use immensely - Celgene, who got it through trials and approval for myeloma, have to keep a very tight patient registry, among other things, and control its distribution carefully. Experience has shown that turning thalidomide loose will always end up with someone (i.e. a pregnant woman) getting exposed to it who shouldn't be - it's gotten to the point that the WHO no longer recommends it for use in leprosy treatment, despite its clear evidence of benefit, and it's down to just those problems of distribution and control.

But in 2010, it was reported that the drug binds to a protein called cereblon (CRBN), and this mechanism implicated the ubiquitin ligase system in the embryonic effects. That's an interesting and important pathway - ubiquitin is, as the name implies, ubiquitous, and addition of a string of ubiquitins to a protein is a universal disposal tag in cells: off to the proteosome, to be torn to bits. It gets stuck onto exposed lysine residues by the aforementioned ligase enzyme.

But less-thorough ubiquitination is part of other pathways. Other proteins can have ubiquitin recognition domains, so there are signaling events going on. Even poly-ubiquitin chains can be part of non-disposal processes - the usual oligomers are built up using a particular lysine residue on each ubiquitin in the chain, but there are other lysine possibilities, and these branch off into different functions. It's a mess, frankly, but it's an important mess, and it's been the subject of a lot of work over the years in both academia and industry.

The new paper has the crystal structure of thalidomide (and two of its analogs) bound to the ubiquitin ligase complex. It looks like they keep one set of protein-protein interactions from occurring while the ligase end of things is going after other transcription factors to tag them for degradation. Ubiquitination of various proteins could be either up- or downregulated by this route. Interestingly, the binding is indeed enantioselective, which suggests that the teratogenic effects may well be down to the (S) enantiomer, not that there's any way to test this in vivo (as mentioned above). But the effects of these compounds in myeloma appear to go through the cereblon pathway as well, so there's never going to be a thalidomide-like drug without reproductive tox. If you could take it a notch down the pathway and go for the relevant transcription factors instead, post-cereblon, you might have something, but selective targeting of transcription factors is a hard row to hoe.

Comments (9) + TrackBacks (0) | Category: Analytical Chemistry | Biological News | Cancer | Chemical News | Toxicology


1. Irrelevant on July 18, 2014 8:01 AM writes...

Wikipedia says Frances is still alive at age 99! That's amazing.

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2. Biotechtranslated on July 18, 2014 9:16 AM writes...

From the wikipedia article on Francis Kelsey:

"In 1960, Kelsey was hired by the FDA in Washington, DC. At that time, she "was one of only seven full-time and four young part-time physicians reviewing drugs" for the FDA."

Wow! How many physicians does the FDA have working for it now? And people wonder why it costs so much to get drugs approved now vs. back in the 60's!

I'm not arguing the level of scrutiny we give new drugs now is a bad thing, it's just amazing how little scrutiny we gave them half a century ago.

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3. Vader on July 18, 2014 9:42 AM writes...

Bit of a tangent, but part of the fallout of thalidomide is that absolutely, positively no one is interested in researching medications to relieve morning sickness.

Which is too bad, because for a small number of women who are particularly susceptible, there's nothing funny about morning sickness. A good treatment would be a wonderful thing.

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4. Vaudaux on July 18, 2014 10:02 AM writes...

Derek, please correct the spelling of Dr Kelsey's first name. She is Frances, not Francis.

"bring on a shiver" is right. I have very clear memories of pictures of armless babies (from a story in Life magazine, I think) shown as part of a science report by one of my classmates in seventh grade, about 1962. I remember hearing that American women who received thalidomide were mostly the wives of servicemen stationed on American military bases in Europe.

Thanks for pointing out that thalidomide racemizes in the circulation. I am one of those who has been glibly citing it as an example of enantiomers with different activities.

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5. Anonymous on July 18, 2014 12:43 PM writes...

Thalidomide was also available in Mexico and some of the US cases derived from crossing the border to get the 'new wonder drug'. (See list: /many-faces-of-thalidomide/ ).

Help me out, please: I'm trying to think of another lawsuit involving the failure to give credit and royalties to the lay-person inventor.

The mother of a child with ADHD, autism or other behavior disorder noticed that the child was much more well behaved after treatment with ??? She had to beg doctors to get more drug (bendectin?) because it was no longer being sold (for safety reasons). She had to beg doctors (at Mass Gen Hosp, I think) to investigate her treatment claims that they repeatedly dismissed as coincidental.

Secretly, the MDs DID do the experiments (off label prescribing), confirmed the mother's own findings and they filed patents WITHOUT INCLUDING THE MOTHER. There was a lawsuit and MGH lost.

I just can't remember the drug or disorder. I think it was in the 1980s or 1990s. I think the treatment has since been discontinued.


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6. Anon on July 19, 2014 3:52 PM writes...

As pointed out by Irrelevant, Frances Kelsey is 99 but did not note that she will be 100 in just 5 days (24th July).

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7. Gary Grayson on July 21, 2014 5:15 AM writes...

It is Frances Kelsey's 100th birthday this week

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8. Søren Furbo on July 22, 2014 3:34 AM writes...

@Vader: Morning sickness is correlated with a lower risk of miscarriage, amongst other things. While I don't think we know the causation, treating it might invite other problems.

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9. DTX on July 30, 2014 4:04 PM writes...

For those of you with access to literature, the best discussion I've seen of the thalidomide disaster is: Mellin et al., The Saga of Thalidomide. NEJM 267(23): 1184-93, 1238-1244, 1962. It tells an interesting story of the horror.

"Biotechtranslated" was right - relatively little scrutiny happened at the time. The Soc of Toxicology was only created in 1960. Thalidomide seemed so much safer than the prior sedatives that doctors had a hard time believing it was dangerous.

If the right animal testing had been done, the disaster would never have happened. However, many people now wish animal testing to cease (and allow disasters like thalidomide to happen again?).

Hence, Biotech's comment leads to an important point, i.e., we have more scrutiny now than in the 1950s for good reason.

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