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Zafgen’s Obesity Drug Shows Promise, Gets Funding

Beloranib. ZGN-433 is the hemioxalate salt of this molecule. (Credit- WHO Drug Information)

Zafgen, whose science has been the subject of much speculation on the Haystack (see earlier posts), has again found favor with investors, despite a tough climate for obesity drug developers. Last week, the company scored $33 million in Series C venture financing to move its drug ZGN-433 (beloranib hemioxalate) into Phase II trials (We found beloranib’s structure in WHO’s drug information Vol. 22, No. 4). This new cash comes on the heels of some fairly promising (albeit early) data the company presented at the June  American Diabetes Association Annual Meeting: in Phase Ib testing, ZGN-433 prompted weight loss without increase in disease biomarkers such as elevated C-reactive protein (an inflammation and hypertension indicator) or heightened LDL “bad” cholesterol .

Despite all that money and early signs of efficacy, plenty of uncertainty remains around the viability of ZGN-433. Zafgen admits that they still don’t know the drug’s exact mode of action in the body.  The drug’s claimed target, methionine aminopeptidase (type 2), is known to play a role in clamping off the blood supply to tumors.  In obese patients, a much lower dose – roughly 100- to 300-fold, claims the FAQ on the company website –  can signal fat tissue to release fatty acids and triglycerides back into the bloodstream; clinical data shows increased levels of breakdown byproducts in blood samples. Further, the drug is currently administered as a twice-weekly subcutaneous injection–not exactly the most user-friendly dosing method.

So what’s so interesting about this drug, from a chemistry perspective?  Well, for one thing, it has two epoxide rings that would normally raise red flags for most med chemists as potential alkylating agents. Many biomolecules have nucleophilic (electron-rich and non-hindered) reactive groups that could be trapped this way, leading to DNA mutations or protein misfolding. And that’s not all: the molecule also has an unsaturated Michael acceptor, a ketone connected directly to a double bond, which usually act as sequestering agents for glutathione in cancer models. These three reactive groups together are uncommon in any lead molecule, and the company has not stated if they observe any protein conjugation as a result.

The ultimate goal would be development of an oral variant of their lead structure, although those second-generation compounds appear to be in the discovery/preclinical phase of development. Only time will tell if these drugs will make it to market; FDA rejection of high-profile obesity drugs Qnexa and Lorcaserin still hang over conversations of new weight-loss drugs.

UPDATE: added structure 5:13PM 7/12, added “hemioxalate” to name of ZGN-433.

2 Comments

  • Jul 13th 201111:07
    by John Beutler

    That’s no ketone, it’s an ester!

  • Jul 13th 201114:07
    by See Arr Oh

    @John Beutler: Yup, you’re right, it sure is. I got caught up trying to describe what constituted a “traditional” Michael acceptor, and forgot to glance back at the structure!

    This system would be less electrophilic than a normal enone, but would still potentially bind to nucleophilic biomolecules.

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