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

第二代芳基烃受体拮抗剂、肌营养不良蛋白调节剂，用于治疗杜氏肌营养不良症

• 批准号: MR/X014118/1
• 负责人: Angela Russell
• 金额: $ 238.62万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FX014118%2F1
• 关键词: Second; generation; arylhydrocarbon; receptor; antagonist

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.

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症杜氏肌营养不良症 (DMD) 中不存在的蛋白质。 Utropin 有潜力作为患者肌营养不良蛋白的替代品并改善疾病。 Ezutromid 是我们实验室开发出来的，是第一种通过增加肌肉中 utropin 的含量来治疗 DMD 的药物。Summit Therapeutics 开始了一项临床试验，以测试 ezutromid 是否对患有 DMD 的男孩有益。治疗 24 周后，临床试验显示出有希望的结果。然而，该药物在较长时间内效果不佳，2018 年，Summit 停止了其开发。因此，我们试图了解 ezutromid 如何发挥作用，以发现替代药物的新机会，这些替代药物可能以类似但更有效的方式发挥作用，并提供长期效果肌营养蛋白增加。我们证明 ezutromid 结合并关闭一种称为芳基烃受体 (AhR) 的蛋白质，从而导致更多的肌营养不良蛋白产生。自从我们的项目开始以来，我们发现了两种新型替代分子，它们可以关闭 AhR 并增加 utropin 的产生。我们还表明，另一种 AhR 结合分子对 DMD 的 mdx 小鼠模型是有益的。我们预计这些分子将克服 ezutromid 的局限性，并且我们将继续将这些分子开发成新的候选药物，作为 utropin 替代疗法。