Corante

About this Author
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: derekb.lowe@gmail.com Twitter: Dereklowe

Chemistry and Drug Data: Drugbank
Emolecules
ChemSpider
Chempedia Lab
Synthetic Pages
Organic Chemistry Portal
PubChem
Not Voodoo
DailyMed
Druglib
Clinicaltrials.gov

Chemistry and Pharma Blogs:
Org Prep Daily
The Haystack
Kilomentor
A New Merck, Reviewed
Liberal Arts Chemistry
Electron Pusher
All Things Metathesis
C&E News Blogs
Chemiotics II
Chemical Space
Noel O'Blog
In Vivo Blog
Terra Sigilatta
BBSRC/Douglas Kell
ChemBark
Realizations in Biostatistics
Chemjobber
Pharmalot
ChemSpider Blog
Pharmagossip
Med-Chemist
Organic Chem - Education & Industry
Pharma Strategy Blog
No Name No Slogan
Practical Fragments
SimBioSys
The Curious Wavefunction
Natural Product Man
Fragment Literature
Chemistry World Blog
Synthetic Nature
Chemistry Blog
Synthesizing Ideas
Business|Bytes|Genes|Molecules
Eye on FDA
Chemical Forums
Depth-First
Symyx Blog
Sceptical Chymist
Lamentations on Chemistry
Computational Organic Chemistry
Mining Drugs
Henry Rzepa


Science Blogs and News:
Bad Science
The Loom
Uncertain Principles
Fierce Biotech
Blogs for Industry
Omics! Omics!
Young Female Scientist
Notional Slurry
Nobel Intent
SciTech Daily
Science Blog
FuturePundit
Aetiology
Gene Expression (I)
Gene Expression (II)
Sciencebase
Pharyngula
Adventures in Ethics and Science
Transterrestrial Musings
Slashdot Science
Cosmic Variance
Biology News Net


Medical Blogs
DB's Medical Rants
Science-Based Medicine
GruntDoc
Respectful Insolence
Diabetes Mine


Economics and Business
Marginal Revolution
The Volokh Conspiracy
Knowledge Problem


Politics / Current Events
Virginia Postrel
Instapundit
Belmont Club
Mickey Kaus


Belles Lettres
Uncouth Reflections
Arts and Letters Daily
In the Pipeline: Don't miss Derek Lowe's excellent commentary on drug discovery and the pharma industry in general at In the Pipeline

In the Pipeline

« Sequenom: Faking It | Main | Nativis: Waiting and Seeing »

June 3, 2010

Eribulin Gets Reviewed, Finally

Email This Entry

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.
200px-Eribulin.svg.png
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 (23) + TrackBacks (0) | Category: Cancer | Regulatory Affairs


COMMENTS

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 Comment

2. 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.
At least it's pirate-resistant. There's no profit in knocking this one off.

Permalink to Comment

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 Comment

4. Chemjobber on June 3, 2010 2:51 PM writes...

Thanks, partial!

Permalink to Comment

5. 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 Comment

6. 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 Comment

7. 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 Comment

8. 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 Comment

9. 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 Comment

10. 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 Comment

11. 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 Comment

12. 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 Comment

13. 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 Comment

14. 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 Comment

15. Anonymous on June 4, 2010 2:48 PM writes...

Sorry for the multiples - problem posting

Permalink to Comment

16. 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 Comment

17. 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 Comment

18. 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 Comment

19. 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 Comment

20. 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 Comment

21. 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 Comment

22. 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....
Yes, I suppose if I was dying, 10 weeks would seem pretty great, but assumes your Q of L is good....

Permalink to Comment

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 Comment

POST A COMMENT




Remember Me?



EMAIL THIS ENTRY TO A FRIEND

Email this entry to:

Your email address:

Message (optional):




RELATED ENTRIES
The Worst Seminar
Conference in Basel
Messed-Up Clinical Studies: A First-Hand Report
Pharma and Ebola
Lilly Steps In for AstraZeneca's Secretase Inhibitor
Update on Alnylam (And the Direction of Things to Come)
There Must Have Been Multiple Chances to Catch This
Weirdly, Tramadol Is Not a Natural Product After All