Zafgen’s ZGN-433 shows promise for obesity- so what’s it look like?
Jan05

Zafgen’s ZGN-433 shows promise for obesity- so what’s it look like?

Just in time to coincide with January's massive uptick in gym-going, Cambridge, MA startup Zafgen has announced good news about its experimental weight-loss drug for severe obesity. The molecule, ZGN-433, helped a small group of severely obese women (with body mass index of 32-45) lose weight- more so than a placebo. Weight losses varied from person to person, but the midpoints of the range of weight loss results were attention-getting: weight loss of 1 kilogram (2.2 pounds) per week, and 3.1 percent of body weight after 26 days, when the trial concluded. Women taking ZGN-433 in the 24-person study also experienced meaningful changes to their triglyceride levels and levels of LDL cholesterol, the so-called "bad cholesterol". The news spurred coverage at FierceBiotech, Xconomy, and many other news outlets. It's too early to tell whether ZGN-433 will become an FDA-approved weight loss drug. But it's encouraging to see companies still plugging away at the obesity problem even in light of the challenging year obesity drugs had in 2010. And Zafgen's announcement today contains some additional tidbits that point interested medicinal chemists toward the kinds of structures Zafgen might be working on. When we last covered Zafgen, the company had revealed the target of its experimental drugs, methionine aminopeptidase 2. And we learned that in animal studies, Zafgen was using a naturally-occurring molecule as a methionine aminopeptidase 2 blocker- fumagillin, or ZGN-201 in the company's parlance. We knew Zafgen was using another molecule in human trials (that's ZGN-433), but at the time the company didn't disclose the molecule's structure, or the name of the company they licensed the molecule from. In today's announcement, Zafgen unveiled that company's name: ZGN-433 was initially developed at Korea's Chong Kun Dang (CKD) Pharmaceuticals. So I decided to perform a Google Patents search to see what kind of structures CKD has patented. My very cursory search revealed four patents but as you can see below, some of the sample structures in the patents differ quite a bit from fumagillin. Zafgen's president and CEO Thomas Hughes told us that fumagillin's long double bond rich tail is troublesome, and it looks like it's gone in both these possibilities. Images: Zafgen and U.S. Patent Office UPDATED: corrected image...

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Zafgen Unveils Target of its Experimental Obesity Drugs: Methionine Aminopeptidase 2- UPDATED
Jun26

Zafgen Unveils Target of its Experimental Obesity Drugs: Methionine Aminopeptidase 2- UPDATED

When I first wrote about obesity drug development back in 2009 I talked with Zafgen, Inc., a biopharmaceutical company working to develop its own obesity medications. At the time, the company was keeping the molecular specifics of what they were doing pretty close to the vest. We knew from Zafgen's website that the company was not targeting the brain like many other obesity drugs do, including lorcaserin, Qnexa, and Contrave, the three big contestants in the obesity drug race. And we knew from articles like Luke Timmerman's in Xconomy that Zafgen's method is inspired by a tumor-shrinking approach developed by the late Judah Folkman and his colleague Maria Rupnick at Children’s Hospital in Boston. Zafgen has never confirmed the molecular target for its experimental obesity drugs. Until today, that is. At the American Diabetes Association's annual meeting in Orlando, Zafgen unveiled that its obesity drug candidates are going after methionine aminopeptidase 2 (MetAP2), a metalloenzyme that clips methionine amino acid residues off of nascent proteins. In addition to announcing the target, Zafgen is presenting data today from two preclinical studies of a methionine aminopeptidase 2 inhibitor, one in obese mice and another in overweight dogs. In short, the studies suggest that inhibiting MetAP2 makes animals shed excess body weight by making adjustments to their fat metabolism and lowering their food intake. "We're overcoming three metabolic adaptations that occur in the obesity setting that make it hard to lose weight," says Tom Hughes, president and CEO of Zafgen. In the long run, the company hopes to develop a pill that can mimic the effects of gastric bypass surgery, a topic C&EN covered earlier this year. But on to the molecules. What's the inhibitor? Well, chemists might find Zafgen's prototype inhibitor familiar: it's the natural product fumagillin, which Zafgen is calling ZGN-201. "Fumagillin has been looked at for a number of indications," Hughes says. We've recently covered a company working on fumagillin analogs for cancer. Fumagillin itself is on the market in France for certain kinds of parasitic infections in HIV patients who have weakened immune systems. And beekeepers use it to control a dysentery-like infection called Nocema disease in beehives. (Bees get diarrhea. Who knew?) Though Zafgen is testing fumagillin in animals, it is not the molecule that Zafgen has carried forward into human clinical trials. The company's ongoing Phase I trial in obese human volunteers is evaluating a different MetAP2 inhibitor Zafgen calls ZGN-433. Hughes won't disclose the structure of ZGN-433 yet. Zafgen licensed it from another company that tried using it to shrink tumors. That didn't work, but the other company (whose name Hughes didn't disclose) already did...

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