Second generation arylhydrocarbon receptor antagonist, utrophin modulators for the treatment of Duchenne muscular dystrophy

Utrophin is a protein closely related to dystrophin, which is the protein that is absent in the muscle-wasting condition Duchenne muscular dystrophy (DMD). Utrophin has the potential to act as a substitute for dystrophin in patients and ameliorate the disease. Ezutromid was developed from work in our labs as the first drug designed to treat DMD by increasing the amount of utrophin in muscle. Summit Therapeutics began a clinical trial to test whether ezutromid would be a beneficial treatment for boys with DMD. The clinical trial showed promising results after 24 weeks of treatment. However, the drug wasn't effective over a longer period and in 2018, Summit discontinued its development. We therefore sought to understand how ezutromid works to uncover new opportunities for alternative drugs that might act in a similar yet more effective way and provide long term increases in utrophin. We demonstrated that ezutromid binds to and switches off a protein, called the arylhydrocarbon receptor (AhR), leading to more utrophin production. Since our project began we have discovered two new types of alternative molecules which switch off AhR and increase utrophin production. We have also shown that an alternative AhR binding molecule is beneficial in the mdx mouse model of DMD. We expect these molecules will overcome the limitations of ezutromid and we will continue to develop these molecules into a new candidate drug as a utrophin replacement therapy.