Development of anti-DUX4 therapeutics for FSHD

描述(由申请人提供)：FSHD在美国影响超过25,000人。按发病率计算，它是第三种最常见的肌营养不良症，但按患病率计算可能是最常见的(Orphanet，2008)。这种疾病被认为是由导致DUX4基因表达的染色质变化以及等位基因特异性PolyA信号稳定DUX4转录本的组合引起的。药理抑制 DUX4活性的变化是开发FSHD治疗方法的一个有吸引力的方法。我们已经证明了DUX4导致C2C12成肌细胞死亡，利用这一方法筛选了20万个DUX4抑制剂的化合物，进行了多次二次筛选，并鉴定了大约640个确认的命中。从这个集合中，我们建议识别那些最有可能开发成药物的化合物。我们将通过合成关键化合物和相关衍生物，并筛选这些化合物对表达DUX4的细胞的活性，开始初步的临床前开发。我们将在基于DUX4条件表达式的小鼠模型中测试其中最有希望的方法。我们的目标是确定1-3个适合继续开发成治疗FSHD的药物的化学系列。

DESCRIPTION (provided by applicant): FSHD affects over 25,000 individuals in the United States. It is the third most common muscular dystrophy by incidence but may be the most common by prevalence (Orphanet, 2008). The disease is thought to be caused by a combination of chromatin changes that cause expression of the DUX4 gene, together with stabilization of the DUX4 transcript by an allele-specific polyA signal. Pharmacological inhibition of DUX4 activity is an attractive approach to developing a therapy for FSHD. We have shown that DUX4 causes cell death of C2C12 myoblasts, used this assay to screen 200,000 compounds for inhibitors of DUX4, performed a number of secondary screens, and identified approximately 640 verified hits. From this set, we propose to identify those compounds with the highest likelihood of being developed into drugs. We will begin preliminary preclinical development by synthesizing key compounds and related derivatives, and screening these for activity on DUX4-expressing cells. We will test the most promising of these in mouse models based on conditional expression of DUX4. We aim to identify 1-3 chemical series suitable for continued development into drugs for the treatment of FSHD.