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 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 safety testing on the compound. Zafgen is using that safety data to enable them to test ZGN-433′s efficacy faster than they otherwise might have.
“Fumagillin itself has limitations as a drug,” Hughes says. It’s not stable and requires refrigeration. The trouble with fumagillin isn’t so much its reactivity, Hughes says. (Fumagillin permanently attaches itself to MetAP2, an unusual-though not unheard of mechanism among drugs).
No, the problem is fumagillin’s long, double-bond-rich tail, which is prone to oxidation. “That can cause mischief,” Hughes says. Back when Folkman and Rupnick were conducting their studies, they didn’t focus on fumagillin. They instead used TNP-470, which replaces that problematic tail with another structure, Hughes says.
So does ZGN-433 look like TNP-470, or is it something else entirely? And will ZGN-433 work in obese humans the way fumagillin has worked in animals? Time will tell.
Structures courtesy of Zafgen