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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 20, 2011

Will Macrocycles Get It Done?

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Posted by Derek

Here's an article from Xconomy on Ensemble Therapeutics, a company that spun off from work in David Liu's lab at Harvard. Their focus these days is on a huge library of macrocyclic compounds (prepared by using DNA tags to bring the reactants together, which is a topic for a whole different post). They're screening against several targets, and with several partners. Why macrocycles?

Well, there's been a persistent belief, with some evidence behind it, that medium- and large-ring compounds are somehow different. Cyclic peptides certainly can be distinguished from their linear counterparts - some of that can be explained by their being unnatural (and poor) substrates for some of the proteases that would normally clear them out, but there can be differences in distribution and cell penetration as well. The great majority of non-peptidic macrocycles that have been studied in biological systems are natural products - plenty of classic antibiotics and the like are large rings. I worked on one for my PhD, although I never quite closed the ring on the sucker.

You can look that that natural product distribution in two ways: one view might be that we have an exaggerated idea of the hit rate of macrocycles, because we've been looking at a bunch of evolutionarily optimized compounds. But the other argument is that macrocycles aren't all that easy to make, therefore evolutionary pressures must have led to so many of them for some good reasons, and we should try to take advantage of the evidence that's in front of us.

What's for sure is that macrocyclic compounds are under-represented in drug industry screening collections, so there's an argument to be made just on that basis. (You do see them once in a while). And the chemical space that they cover is probably not something that other compounds can easily pick up. Large rings are a bit peculiar - they have some conformational flexibility, in most cases, but only within a limited range. So if you're broadly in the right space for hitting a drug target, you probably won't pay as big an entropic penalty when a macrocycle binds. It already had its wings clipped to start with. And as mentioned above, there's evidence that these compounds can do a better job of crossing membranes than you'd guess from their size and functionality. One hope is that these properties will allow molecular weight ranges to be safely pushed up a bit, allowing a better chance for hitting nontraditional targets such as protein-protein interactions.

All this has led to a revival of med-chem interest in the field, so Ensemble is selling their wares at just the right time. One reason that there haven't been so many macrocycles in the screening decks is that they haven't been all that easy to make. But besides Liu's DNA templating, some other interesting synthetic methods have been coming along - the Nobel-worthy olefin metathesis reaction has been recognized for some time as a good entry into the area, and Keith James out at Scripps has been publishing on macrocyclic triazoles via the copper-catalyzed click reaction. Here's a recent review in J. Med. Chem., and here's another. It's going to be interesting to see how this all works out - and it's also a safe bet that this won't be the only neglected and tricky area that we're going to find ourselves paying more attention to. . .

Comments (31) + TrackBacks (0) | Category: Chemical News | Drug Development


1. Terry Liu on July 20, 2011 12:38 PM writes...

It is great some one have interesting to macrocycles, I am particularly interested in this topic since I spend several years time to study a cyclization reaction.
Regard to David Liu’s research, it is too frontier to me, an organic chemist. I guess most of ppl here cant really understand their reaction and meaning of DNA research.

Now let’s back to the macrocycles research, indeed I found there are several macrocycle drugs on market. Bearing a unique structure compared to other type of compounds, it should be treated with more attention.
Here is the most recent review about the macrocycles in drug discovery, hope you can like it.

Nature Reviews Drug Discovery 7, 608-624 (July 2008) | doi:10.1038/nrd2590

More than 100,000 natural-product secondary metabolites are known to exist, and of these, approximately 3% are macrocycles Despite the low percentage of macrocycles, this class of natural products includes a subset of powerful therapeutics that are used to modulate immune-system responses, to fight evolving infectious organisms and to treat cancer.

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2. anchor on July 20, 2011 12:41 PM writes...

I say, why not? With so many natural macrocyclic products in use (Erythromycins and other macrolide based antibiotics, Vancomycin, caspofungins etc.) we should boldly march on to these newer areas. As for the price of "fabricated macrocycles"...a topic to be discussed on another day.

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3. Terry Liu on July 20, 2011 12:44 PM writes...

Sorry, here is the title of that review!

The exploration of macrocycles for drug discovery — an underexploited structural class

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4. Pamplemousse on July 20, 2011 12:56 PM writes...

That nature reviews paper is good; I was just coming in to post it as well.

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5. daen on July 20, 2011 1:06 PM writes...

Regard to David Liu’s research, it is too frontier to me, an organic chemist. I guess most of ppl here cant really understand their reaction and meaning of DNA research.

DNA (or RNA) templated synthesis is not a new technology, nor especially hard to grasp. Every DNA/RNA-templated synthesis company that I know of which started in the last ten years can trace their pedigree back to the Schultz lab at Scripps - Ensemble, Praecis, Nuevolution, Vipergen.

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6. Anonymous on July 20, 2011 1:17 PM writes...

Someone should take a look at good drugs that violate all or most of that plague on our houses: the 5 Comandments. Just maybe we will find some other exciting new guidelines for drug design.

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7. ANON on July 20, 2011 1:20 PM writes...

The concept of trying to explore macrocycles has been recognized and explored by academic groups and Pharma already for years. It is not new. GSK, for example, had an entire group that was focussed in this area of chemistry, and later divested the group after several years as so little emerged from the chemistry being explored.

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8. Innovorich on July 20, 2011 1:27 PM writes...

Macrocycles definitely good for some flat, exposed binding pocket/PPI-like targets, e.g. HCV protease.

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9. Joe Mamma on July 20, 2011 1:34 PM writes...

Macrocycles & HDACs

J. Am. Chem. Soc., 2010, 132 (47), pp 16962–16976

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10. Joe Mamma on July 20, 2011 1:35 PM writes...

Macrocycles & HDACs

J. Am. Chem. Soc., 2010, 132 (47), pp 16962–16976

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11. JB on July 20, 2011 2:28 PM writes...

Conveniently I used to be in the Liu group, then Ensemble, and now I'm in the Broad group referenced in the above JACS paper. The Ensemble team also wrote a Nature Reviews piece on this a couple years ago, PMID 18591981. At Broad we have a number of macrocycles in various stages of hit to lead development, including a disproportionate number in antimicrobials- there seems to be some bias for activity in that area even though the compounds generally have low mammalian cytotox.
Incidentally, I'm also looking for a manager for coordinating CM and analytical in our screening group, so any chemists who have experience in those areas should contact me.

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12. Ensemble scientist on July 20, 2011 2:52 PM writes...

Thanks for the shout out! The main challenge with macrocycles is being able to modulate their conformational complexity so that the binding epitopes are in the right place.

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13. Rick on July 20, 2011 3:22 PM writes...

One potential advantage of macrocycles, in my mind at least, is that they are, relatively speaking, more constrained than any linearized version of the same molecule. Since big linear molecules (> 700 Da) with lots of single bonds in the main chain can bend and twist quite a bit in solution and most of those states aren't conducive to target binding, anything that constrains their freedom of movement, assuming the binding configuration is still allowable, would improve binding affinity. I'm not aware of evidence for this, but I haven't tried looking either, but it seems like an easily testable hypothesis.

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14. Boghog on July 20, 2011 4:08 PM writes...

High MW compounds like macrocyclic antibiotics may still be orally available if rigid according to:

Daniel Veber
J Med Chem. 2002 Jun 6;45(12):2615-23
DOI: 10.1021/jm020017n PMID: 12036371

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15. drug_hunter on July 20, 2011 7:31 PM writes...

In the past two years there have been sessions at various chemistry meetings on "rule-breaker" compounds (i.e. molecules that fail Ro5). I find these sessions quite interesting and it seems that people are getting a little more comfortable venturing out of the box! Remember, cyclosporine is orally bioavailable!

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16. pharmadude on July 20, 2011 8:13 PM writes...

High throughput sequencing: Cool
DNA encoded combinatorial chemistry: Cool
Marcocycles: Not as cool as people think they are

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17. gippgig on July 20, 2011 8:20 PM writes...

Macrocycles are pretty easy to biosynthesize by the polyketide pathway (see type I PKS).

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18. mehcaver on July 21, 2011 4:11 AM writes...

Ditto, gippgig. It's interesting that polyketide biosynthesis parallels that of fatty acids. As I recall, cyclic peptide biosynthesis also utilizes an acyl carrier protein to ferry the growing chain around the peptide synthases. Just for the sake of speculation, but has any work been done to modify the specificities of these enzyme systems/complexes to fashion designer macrocycles? For example, to create macrocyclic "skeletons" that are particularly easy to modify via in-vitro chemistry? If the hard part is closing the ring, why not let the bugs do it, then modify the "side chains" yourself?

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19. petros on July 21, 2011 4:39 AM writes...

Having seen Nick Terret (CSO of Ensemble) present on this work.It is a fascinating approach that seems to be delivering selectivity as well as reasonable potency. One of the key problems will of course be sorting out delivery issues.

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20. Rick on July 21, 2011 8:32 AM writes...

@ pharmadude (#16) That's sooooo 90's, dude! :)

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21. HelicalZz on July 21, 2011 8:33 AM writes...

There is only a very limited value to a chemistry technique that doesn't effectively scale well.

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22. geezer on July 21, 2011 9:23 AM writes...

@18 .."but has any work been done to modify the specificities of these enzyme systems/complexes to fashion designer macrocycles?"

Kosan Biosciences was founded on this principle. Unnatural natural products.

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23. JAB on July 21, 2011 11:05 AM writes...

And.......the epothilones are macrolides one of which made it to market for cancer. BMS has ixabepilone, Kosan/Roche, Novartis, and Bayer all had compounds at least in phase I trials.

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24. Fred on July 21, 2011 1:39 PM writes...

Wait, you never closed the ring and they STILL awarded your PhD?? Tsk tsk, where are the standards!

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25. Hap on July 21, 2011 1:44 PM writes...

Macrocyclization used to be a lot harder before Yamaguchi macrocyclizations, ring-closing alkene and alkyne metatheses, Stille couplings, and alkyne-azide cycloadditions.

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26. Texascarbon on July 21, 2011 9:20 PM writes...

@ geezer: outstanding observation- gippgig and mehcaver, check out the relevant academic work by Khosla and others - it was was inspirational. At some point I stopped following along but what I remember is that the approach had a scaling problem. Did this get resolved?
@ HelicalZz: great point, but good ol RCM certainly isn't among those that doesn't scale. For a lovely read, see grubbs' Nobel lecture and you will find a delightful example in drug development, along with many other things. Certainly this reaction could continue to fuel alot of effort in macrocyclic drug discovery.
To me, nature has taught us a lesson through her macrolides and cyclic peptides. They don't follow the rules and they can do some pretty cool things. The idea of having a diverse set in a screening collection seems like a good one to me. Especially with the way MDR bugs have become a real issue in human health.

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27. MedKemikal on July 22, 2011 8:53 AM writes...

Of course Ensemble sells macrocycles!

A DNA-encoded synthesis technology is only amenable to polymeric structures, because all the monomers need have a second functional group to be stuck onto a DNA piece. Which means peptides. But no one wants peptides (or maybe that's changing), so they just cyclize it, and ugly peptide turns into beautiful macrocycle.

All this DNA-encoded stuff is going the way of 90's combi dinosaurs!

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28. pharmadebunker on July 22, 2011 9:17 AM writes...

Ensemble at the cutting edge?

If so they why did their "scientists" buy in to the snake oil that Solulink sells?

Unstable hydrazones as conjugation linkers!!??


Pyridyl hydrazines !!??

"ease of use conjugation" um sure yeah when your using hydrazine, too bad they won't stay together.

Read more about Solulink at

Come on Ensemble, really?

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29. pharmadude on July 30, 2011 2:17 PM writes...

@27. There's no inherent connection between DNA encoded libraries and peptides. That's the job of chemists, to find a way to make use of high throughput sequencing technology. As a chemist you should not look at a new technology and conclude that due to a chemistry limitation the field can't advance. Instead, as a chemist your job is to find a way around what appears to be a synthetic limitation. That, afterall, is what research is. Otherwise you're just making shit in a lab using existing methodologies...which makes you a technician. Sadly that's what most chemists are these days, technicians and not researchers.

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30. vasanth on November 11, 2011 9:47 PM writes...


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31. Jane Yao on July 17, 2012 7:13 PM writes...

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