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

Research Outcomes: Public Summary

 Beloranib was the most effective therapeutic ever tested for PWS, causing significant weight loss and improvements in behavioral symptoms. Unfortunately, the development of beloranib was halted due to safety issues related to blood clotting. Further development of beloranib-related drugs has proven impossible because we fundamentally do not know how or why beloranib causes weight loss. In our research project funded by FPWR we sought to understand the specific mechanism of action of beloranib, in the hope that by deeply understanding how it works, we can enable the development of new drugs which capture beloranib’s efficacy while avoiding its toxicity.
We made a number of key findings over the course of the project. First, we found that beloranib’s mechanism of action does not require the appetite-suppressing hormone GDF15. We originally found that Beloranib increases GDF15 levels in the blood, and thus hypothesized that it may play a role in appetite suppression by beloranib. However, when we treated mice that lacked either GDF15 or the GDF15 receptor GFRAL with beloranib, we found they still lost weight and suppressed food intake similar to control mice. Many pharmaceutical companies are developing GDF-15 related therapeutics for weight loss. Because beloranib and GDF-15 work through independent mechanisms, future dual therapeutic strategies with these two classes of drugs may be worthwhile for testing.
Second, we identified a number of key proteins in the body that mediate beloranib’s effects. By performing genetic screens and pharmacologic assays in human cells and targeted genetic manipulations in mice, we identified 4 proteins that are key mediators of appetite suppression by beloranib. For one of these key mediators, when we overexpressed it specifically in neurons of mice we were able to alter their body weight by over 40%. This protein has not been implicated in the control appetite before, and we think it represents an exciting new potentially druggable target for obesity and PWS. These results have substantially improved our understanding of how beloranib works and get us closer to the development of next-generation beloranib-class drug development.
Third, we have tested the hypothesis that beloranib may bind more that one protein target in the body. Beloranib binds and inhibits a protein call methionine aminopeptidase 2 (MetAP2). While it has long been thought that inhibiting MetAP2 causes reduced food intake and weight loss, we have discovered that MetAP2 may actually not be the relevant of target of beloranib. It is not uncommon for drugs to bind more than one protein, and we have been working on finding other binding partners of beloranib because we hypothesize that these other targets, not MetAP2, may be the relevant drivers of weight loss. We performed several target identification experiments and have converged on a new candidate protein that we think beloranib may be binding. We are excited to further test and validate whether this protein represents a new target of beloranib.
Overall, our work has significantly expanded our understanding of how beloranib works at the molecular level. Through both elucidating the molecular pathways that beloranib affects, and probing the proteins beloranib physically interacts with, we have generated a new set of potential druggable targets that may hold promise for the treatment of PWS.