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Chemical Biology

Zafgen’s Epoxide Adventure

Zafgen is a startup in the Boston area that’s working on a novel weight-loss drug called beloranib. Their initial idea was that they were inhibiting angiogenesis in adipose tissue, through inhibition of methionine aminopeptidase-2. But closer study showed that while the compound was indeed causing significant weight loss in animal models, it wasn’t through that mechanism. Blood vessel formation wasn’t affected, but the current thinking is that Met-AP2 inhibition is affecting fatty acid synthesis and causing more usage of lipid stores.
But when they say “novel”, they do mean it. Behold one of the more unlikely-looking drugs to make it through Phase I:
Natural-product experts in the audience might experience a flash of recognition. That’s a derivative of fumagillin, a compound from Aspergillus that’s been kicking around for many years now. And its structure brings up a larger point about reactive groups in drug molecules, the kind that form covalent bonds with their targets.
I wrote about covalent drugs here a few years ago, and the entire concept has been making a comeback. (If anyone was unsure about that, Celgene’s purchase of Avila was the convincer). Those links address the usual pros and cons of the idea: on the plus side, slow off rates are often beneficial in drug mechanisms, and you don’t get much slower than covalency. On the minus side, you have to worry about selectivity even more, since you really don’t want to go labeling across the living proteome. You have the mechanisms of the off-target proteins to worry about once you shut them down, and you also have the ever-present fear of setting off an immune response if the tagged protein ends up looking sufficiently alien.
I’m not aware of any published mechanistic studies of beloranib, but it is surely another one of this class, with those epoxides. (Looks like it’s thought to go after a histidine residue, by analogy to fumagillin’s activity against the same enzyme). But here’s another thing to take in: epoxides are not as bad as most people think they are. We organic chemists see them and think that they’re just vibrating with reactivity, but as electrophiles, they’re not as hot as they look.
That’s been demonstrated by several papers from the Cravatt labs at Scripps. (He still is at Scripps, right? You need a scorecard these days). In this work, they showed that some simple epoxides, when exposed to entire proteomes, really didn’t label many targets at all compared to the other electrophiles on their list. And here, in an earlier paper, they looked at fumagillin-inspired spiroexpoxide probes specifically, and found an inhibitor of phosphoglycerate mutase 1. But a follow-up SAR study of that structure showed that it was very picky indeed – you had to have everything lined up right for the epoxide to react, and very close analogs had no effect. Taken together, the strong implication is that epoxides can be quite selective, and thus can be drugs. You still want to be careful, because the toxicology literature is still rather vocal on the subject, but if you’re in the less reactive/more structurally complex/more selective part of that compound space, you might be OK. We’ll see if Zafgen is.

21 comments on “Zafgen’s Epoxide Adventure”

  1. See Arr Oh says:

    Great update! Looking for more? Check out our Haystack post from last year:’-money-less-problems/

  2. Old Lab Rat says:

    For a bit of precedent for epoxide containing drugs, recall eplerenone

  3. lynn says:

    Fosfomycin – amazingly specific:

  4. Paul says:

    You have a bad link at “>here”.

  5. PharmaHeretic says:

    Though this one is about grad school in astrophysics, the subject matter is relevant to other sciences.
    “Controversy has erupted after a departmental email from faculty to astrophysics graduate students was leaked. Key tips for success in grad school include: ‘However, if you informally canvass the faculty (those people for whose jobs you came here to train), most will tell you that they worked 80-100 hours/week in graduate school. No one told us to work those hours, but we enjoyed what we were doing enough to want to do so…If you find yourself thinking about astronomy and wanting to work on your research most of your waking hours, then academic research may in fact be the best career choice for you.’

  6. Puff the Mutant Dragon says:

    Wow. two epoxide rings and a michael acceptor. and it’s a freaking weight loss drug admin via subcutaneous injection. i have to admit i’m impressed. if it makes it to the clinic will be even more so.

  7. AnotherAmideLibrary says:

    Reminds me of a cockroach pheromone…

  8. Chemist For Life says:

    @ 6 – Puff – are you prepared to be even more impressed? The compound under discussion is already in the clinic…

  9. fat old man says:

    If it’s in the clinic I believe that means it was Ames negative. Does that surprise anyone considering its functional group reactivity? Are there other Ames negative epoxides?

  10. Insilicoconsulting says:

    Coincidence..damn well it is. Had a meeting with the “recently acquired ” covalent drugs company just yesterday.
    They claim to have drugs/leads that are very specific/hardly any significant off-target activity , “almost” non-toxic and with very nice pk.
    From what I understand, The key is to have a scale of functional group reactivity vs AA residues and try and target non-enzymatic activity/allosteric pockets.

  11. David Borhani says:

    Just one word (on epoxides): Scopolamine

  12. Bioinvestor says:

    They presented their 28-day weight loss data last week at BIOinvestor. Efficacy data was quite impressive and it had a pretty clean AE profile. Only caveat was the small numbers in this study (30ish). It will be interesting to follow this one

  13. cliffintokyo says:

    Not too surprising that when you *put* an epoxide into a larger molecule, the reactivity gets “diluted”, and the electrophilic selectivity is enhanced (by 3D fit, steric hindrance, probability of correct orientation for attack, neighboring group effects, etc).
    So, are you synthesising epoxides now Derek? 😉

  14. newnickname says:

    @5 PharmaHeretic: “No one told us to work those hours, but we enjoyed what we were doing enough to want to do so.” Off the Zafgen topic but on the RBW topic …
    A famous-in-his-own-right RBW PhD was telling me of working in the lab on a Sat night / Sun morning when RBW, Gilbert Stork and their wives unexpectedly dropped in after a night of clubbing, around 2 AM.
    I already knew the answer but asked if he was there due to peer pressure, RBW pressure, etc.. Of course not. He and others were there because that’s where they loved to be. In many cases, that love of science is requited (position, career, etc.); in many other cases it is not.

  15. Pete says:

    As well as getting bringing the epoxide carbon into contact with a nucleophilic atom in the protein, you’ll probably also need something nearby to stabilise (or neutralise) the negatively charged oxygen. The associated geometric contraints will need to be satisfied with the rest of the molecule making effective contacts with the protein. As Drug Discovery becomes more difficult we really need to ask ourselves what we really know about compound quality.

  16. Russ Petter says:

    I suspect that the structure of beloranib, as depicted, is incorrect. The sidechain epoxide in fumagillin is an allylic epoxide, not vinylic. If beloranib is prepared via semi-synthesis from fumagillin, it is unlikely that the sidechain was truncated during the synthesis.

  17. ck says:

    @Pete: that is exactly what happens. The spiroepoxide oxygen is most likely protonated by a water molecule that is bound to the two (or one) active site metals. See doi: 10.1074/jbc.M305325200 for a theoretical/experimental study. The epoxide is also perfectly located in MetAP-2, as compared to the other isoform (MetAP-1), which is quite resistant towards alkylation. The flexibility of the alkylated histidine residue appears to play a role in this, it is more fixed in the non-sensitive isoform.
    Fosfomycin, as mentioned above, is another prime example of an epoxide that is perfectly “tuned” to its target, MurA. It is given in gram-doses, even to pregnant women, and shows no off-target reactivity. It is even not always easy to get fosfomycin to react with nucleophiles in vitro.

  18. Chemist For Life says:

    “Thunder God Vine Drug Zaps Pancreatic Cancer”
    Here’s another interesting example of an “epoxide” (no less than three of them) containing molecule with clinical aspirations… Phase I is scheduled to commence by the end of the year (pending FDA approval of IND).
    “Minnelide” is a more soluble prodrug of the natural occurring diterpenoid epoxide, Triptolide.
    Triptolide is isolated from the Chinese “Thunder God Vine” (Tripterygium wilfordii). Coming from a plant with a name like that it has to succeed, right…? Go crush those tumors!

  19. eugene says:

    One of those epoxides is tertiary… and the other one is protected by the phenyl ring hanging on the other side of that ester. Maybe the ester bond has to be hydrolized first before the epoxide can react with the target?

  20. PotStirrer says:

    @16 Structure is definitely wrong. Another CH2 needs to be inserted between the trisubstituted epoxide and the alkene.

  21. anonymous says:

    Several comments above have it right: the epoxide functionality really lies in the “grey zone” between pure (very reactive) protein alkylating agents and “mechanism based irreversible, or “suicide” inhibitors” that require enzyme-mediated chemistry to generate the reactive species. The exact structure of the epoxide (i.e., how sterically hindered it is), and just how nucleophilic a protein’s amino acid side chains are, will define just what shade of grey you’re talking about .

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