Determining beloranib’s mechanism of action to inform novel drug targets for Prader-Willi syndrome

Funding Summary

Dr. Mitchell and her team have been investigating how beloranib, a drug that effectively reduced hyperphagia and induced weight loss in individuals with PWS, worked. By defining downstream effectors of beloranib’s hyperphagia-reducing action, they hope to identify a safe and effective drug to treat hyperphagia in PWS.

Dr. Theresa Strong, Director of Research Programs, explains the details of this project in this video clip.


Lay Abstract

A key feature of Prader Willi Syndrome (PWS) is compulsive overeating, which leads to severe obesity, obesity-associated health complications and shortened life expectancy. There are currently no approved drugs which can treat obesity in people with PWS. In 2015 a drug called beloranib showed great promise in a clinical trial but was not developed further due to safety issues. In PWS patients, beloranib caused significant weight loss and improved compulsive eating behavior and to date, no other drug has been as effective as beloranib.
Although clinical development of beloranib was halted, it is critical study beloranib so that we can understand how it works. This research may be the key to developing more effective ‘beloranib-like’ therapeutics which do not have the same safety issues. Our research over the past 5 years has focused on characterizing the molecular mechanism of action of beloranib and next-generation drugs derived from beloranib. The ultimate goal of our research program is to understand how beloranib works so we can develop ‘beloranib-like’ drugs, which are safer and can be quickly moved into clinical trials for PWS patients.
We have made significant progress and support from the Foundation for Prader Willi Research will help us continue these important studies. Beloranib is known to inhibit the protein MetAP2, and it was assumed that MetAP2 inhibition was the reason for weight loss. However, we recently discovered that MetAP2 is not needed for beloranib to be effective. We also identified a key molecular pathway that is needed for beloranib to be effective. In this project we will build on these two key observations.
First, we will look for the relevant target of beloranib by measuring what proteins beloranib binds to. Second, we will test whether activating the molecular pathway affected by beloranib can alter compulsive eating behavior and cause weight loss. These complementary approaches will help us to identify the specific proteins responsible for beloranib’s weight loss effects. If successful, the next step would be to use a combination of computational techniques and high throughput screening to identify drugs that can safely target these key proteins.
Based on our previous work on this project, we believe that it is possible to develop therapeutics which mimic beloranib’s mechanism of action while avoiding safety issues. Our work has the potential to directly lead to such drugs and our long-term goal is to identify a lead drug candidate that is suitable for clinical trials.

This project has been made possible by funding from FPWR-Canada

Funded Year:


Awarded to:

Sarah Mitchell, Ph.D.




Princeton University


Sarah Mitchell, PhD

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