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

肌营养不良蛋白是一种与肌营养不良蛋白密切相关的蛋白质，肌营养不良蛋白是肌肉萎缩性疾病杜氏肌营养不良症（DMD）中不存在的蛋白质。Utrophin有可能作为患者中肌营养不良蛋白的替代品并改善疾病。依珠曲米德是从我们实验室的工作中开发出来的，是第一种通过增加肌肉中utrophin的含量来治疗DMD的药物。Summit Therapeutics开始了一项临床试验，以测试依珠曲米德是否会对DMD男孩有益。临床试验在治疗24周后显示出有希望的结果。然而，该药物在较长时间内无效，2018年，Summit停止了其开发。因此，我们试图了解ezutromid如何工作，以发现替代药物的新机会，这些药物可能以类似但更有效的方式发挥作用，并提供长期增加utrophin。我们证明，ezutromid结合并关闭一种称为芳香烃受体（AhR）的蛋白质，导致更多utrophin的产生。自从我们的项目开始以来，我们已经发现了两种新型的替代分子，它们可以关闭AhR并增加utrophin的产生。我们还表明，另一种AhR结合分子在DMD的mdx小鼠模型中是有益的。我们期望这些分子将克服依唑曲米德的局限性，我们将继续将这些分子开发成一种新的候选药物，作为utrophin替代疗法。

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.