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June 3, 2010
Eribulin Gets Reviewed, Finally
Posted by Derek
So it looks like the FDA is giving reviewing Eisai's oncology drug Eribulin (E7389) a priority review. The company had hoped to get it reviewed three years ago, but the FDA told them to get back into the clinic and collect more data.
The compound is being reviewed for advanced breast cancer, and the earlier clinical data looked pretty good. (Head and neck tumors, on the other hand, didn't show much of a response). It binds to yet another site on tubulin (a popular site for various oncology agents), but in a rather complicated fashion that differs from the other agents in this category.
The compound is remarkable mainly for its brutal structural complexity, and for the fact that it's being made synthetically. It looks like a natural product, for sure, but it's actually a modified version of the right-hand side of halichondrin B, whose structure is still more horrific. Kishi's group at Harvard synthesized that beast back in 1992, and that work was the foundation of the synthesis of Eribulin. I don't think this is necessarily going to spark a renaissance of Big Natural Product Analog Synthesis inside the pharma labs, but it's quite a story. Here's hoping it has a good ending - we should know in September.
Comments (24)
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1. Chemjobber on June 3, 2010 10:51 AM writes...
I'm not aware of any published accounts of the synthesis, bench- or process-scale. Anyone else?
Permalink to Comment2. barry on June 3, 2010 11:10 AM writes...
the recent development of Provenge may mean that Cost-of-Goods is much less important than chemists like to think. Or it might not. This is going to depend on Health Care decisions Americans haven't even started to discuss yet.
Permalink to CommentAt least it's pirate-resistant. There's no profit in knocking this one off.
3. partial agonist on June 3, 2010 1:03 PM writes...
chemjobber,
The most complete synthetic paper was last year in JACS: JACS 2009, 131, 15636–15641.
While this s not a "process paper" it does try to make the point that it is scable and cost-effective (relatively speaking I guess). One would presume that the Eisai process route is pretty darn similar.
Permalink to Comment4. Chemjobber on June 3, 2010 2:51 PM writes...
Thanks, partial!
Permalink to Comment5. Dave_n on June 3, 2010 4:12 PM writes...
Part of the eribulin story was given in the book Anticancer Agents from Natural Products, Chapter 13 under the code name E7389 in 2005, and was reported orally at an AACR Meeting by both NCI and Eisai in 2007. It has also been published in parts by the Eisai scientists using the old Woodward technique of a 2 pager covering the total synthesis of Chlorophyll A in JACS.
Permalink to Comment6. JCWNl on June 3, 2010 9:08 PM writes...
its amazing how some molecules look so, how shall i say it, anti cancer =-)
Permalink to Comment7. quintus on June 4, 2010 2:46 AM writes...
There is a good review in Chem. Rev. 2009, 109, 3044 which describes both the Halichondrins and E7389
Permalink to Comment8. rogi on June 4, 2010 9:26 AM writes...
There is another natural product antibotic, Thienomycin, (Primaxin)synthesized by the Merck group in the 80's which is constructed by total synthesis. It is a 15 step slog which is econonmically viable. The intermediates are farmed out and put together at Merck. It never was a blockbuster droug,but has consistantly clocked 250-350M yearly for the company. Additionally, though the patent has expxirted, nobody is copying it due to its compexity AND the trade secret elements in puting it together.
Permalink to Comment9. Anonymous on June 4, 2010 2:27 PM writes...
Out of curiosity anyone have a guess at the current "record holder" for the drug produced by totsyn with the greatest number of synthetic steps?
Permalink to Comment10. Anonymous on June 4, 2010 2:31 PM writes...
Out of curiosity anyone have a guess at the current "record holder" for the drug produced by totsyn with the greatest number of synthetic steps?
Permalink to Comment11. Anonymous on June 4, 2010 2:31 PM writes...
Out of curiosity anyone have a guess at the current "record holder" for the drug produced by totsyn with the greatest number of synthetic steps?
Permalink to Comment12. Anonymous on June 4, 2010 2:35 PM writes...
Out of curiosity anyone have a guess at the current "record holder" for the drug produced by totsyn with the greatest number of synthetic steps?
Permalink to Comment13. Anonymous on June 4, 2010 2:37 PM writes...
Out of curiosity anyone have a guess at the current "record holder" for the drug produced by totsyn with the greatest number of synthetic steps?
Permalink to Comment14. Nitricoxide99 on June 4, 2010 2:39 PM writes...
Out of curiosity anyone have a guess at the current "record holder" for the drug produced by totsyn with the greatest number of synthetic steps?
Permalink to Comment15. Anonymous on June 4, 2010 2:48 PM writes...
Sorry for the multiples - problem posting
Permalink to Comment16. David Young on June 4, 2010 11:55 PM writes...
There is another natural product antibotic, Thienomycin, (Primaxin)
To be specific, Primaxin is a combination of a derivative of Thienomycin (imipenem) and Cilistatin.
Permalink to Comment17. processchemist on June 5, 2010 2:07 AM writes...
@nitricoxide99
Currently fondaparinux (non natural, synthetic) should be the record owner (18 steps, I think).
Permalink to Comment18. Anon on June 5, 2010 2:30 AM writes...
Check out the synthesis of the old Organon pentasacharide anticoagulant at the bench it was at least 30 steps
Permalink to Comment19. Medchem on June 5, 2010 2:34 AM writes...
The trade-secret remark above started me thinking if the pharma industry could do more of this. Might make an interesting blog if there is any evidence that it can work to help protect you ip. Must admit I have not heard of any examples myself.
Permalink to Comment20. anon on June 5, 2010 10:48 AM writes...
18. Try 56 steps!
Commercialized in 2002, fondaparinux was "the first synthetic low-molecular-weight heparin drug that reached the market," said Stan van Boeckel, Organon's head of medicinal chemistry. Carbohydrates are notoriously difficult to synthesize, and fondaparinux is a poster child for synthetic complexity: Making it takes 56 steps. "It is, due to its lengthy synthesis and highly rich molecular structure, the most complex synthetic drug currently available commercially," van Boeckel said.
Permalink to Comment21. Chemjobber on June 5, 2010 1:30 PM writes...
#14: Trimeris is Roche's protein that's made via solid-phase synthesis: it's 106 steps.
http://pipeline.corante.com/archives/2002/08/08/better_them_than_me.php
Permalink to Comment22. Jose on June 7, 2010 3:41 AM writes...
Some results just released.... apparently extends median survival time by "about 2.5 months."
Ooooohhhhhh! Wow! 10 weeks! Bravo for statistics validating an essentially irrelevant clinical outcome....
Permalink to CommentYes, I suppose if I was dying, 10 weeks would seem pretty great, but assumes your Q of L is good....
23. InfMP on June 8, 2010 6:26 PM writes...
10.1021/ja9058475
10.1021/ja9058487
This is the double JACS full article on the synthesis of the Easai compound
10.1021/ja905843e
this is the one that came out a couple weeks before about the ligand design for the NHKs
Permalink to Comment24. Ilene Hitzler on March 1, 2012 3:18 PM writes...
Hi, I think your blog might be having browser compatibility issues. When I look at your website in Safari, it looks fine but when opening in Internet Explorer, it has some overlapping. I just wanted to give you a quick heads up! Other then that, amazing blog!
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