Screen for MURF-1 inhibitors to treat myopathy

描述（由申请人提供）：肌肉萎缩（萎缩），也称为肌病，是许多疾病的临床并发症，例如，癌症、艾滋病和糖尿病，以及不活动和衰老的自然后果;它显著降低生活质量。一组称为atrogins（萎缩特异性基因）的新基因的表达在禁食生物体的骨骼肌中急剧增加，并在恢复进食后迅速减少。其中之一，MuRF-1（肌肉特异性环指-1），已被确定为E3泛素连接酶，是萎缩相关的加速蛋白水解的组分。泛素途径酶被认为是用于多种适应症的优异分子靶标。因此，MuRF-1是用于预防或逆转与各种病理学相关的肌肉萎缩的有吸引力的靶标。Progenra建议利用在I期开发的检测方法筛选小分子文库，以鉴定MuRF-1的抑制剂并对其进行化学优化。在该补充项目中，拟通过在功能试验中表征选定的抑制剂，包括基于细胞的（C2 C12肌管）试验和肌肉萎缩的体内疗效模型，扩大II期项目的范围，缩短MuRF-1抑制剂的临床前开发时间。MuRF-1的临床候选抑制剂的鉴定是开发一类新的肌肉萎缩靶向疗法的第一步。这些疗法应有效治疗与衰老、癌症、糖尿病和其他慢性疾病相关的肌肉萎缩。 公共卫生相关性：肌肉萎缩（消瘦），也称为肌病，是许多疾病的临床并发症，例如，癌症、艾滋病和糖尿病，以及不活动和衰老的自然后果;它显著降低生活质量。Progenra开发了一种筛选试验，以寻找与肌肉蛋白质降解相关的酶（称为MuRF-1）的抑制剂。第二阶段的工作将包括使用这种检测方法来寻找合适的抑制剂，并通过应用药物化学使它们成为药物样。在这个补充项目中，这些最好的MuRF-1抑制剂将在肌肉萎缩的细胞和动物模型中进行测试，作为其临床前开发的第一步;这将缩短将其投入临床试验所需的时间。最终，这些化合物之一可能会进入临床和市场，用于治疗肌肉萎缩。

DESCRIPTION (provided by applicant): Muscle atrophy (wasting), also known as myopathy, is a clinical complication of many diseases, e.g., cancer, AIDS, and diabetes, as well as a natural consequence of inactivity and aging; it significantly diminishes quality of life. The expression of a group of novel genes called atrogins (atrophy-specific genes) increases dramatically in skeletal muscles of fasting organisms and decreases rapidly upon resumption of feeding. One of these, MuRF-1 (Muscle-specific RING Finger- 1), has been identified as an E3 ubiquitin ligase that is a component of atrophy-associated accelerated proteolysis. Ubiquitin pathway enzymes are considered excellent molecular targets for diverse indications, Thus, MuRF-1 is an attractive target for preventing or reversing muscle wasting associated with various pathologies. Progenra proposes to utilize an assay developed in Phase I to screen small molecule libraries to identify inhibitors of MuRF-1 and optimize them chemically. In this supplemental project, it is proposed to extend the scope of the Phase II project and shorten the preclinical development time of MuRF-1 inhibitors by characterizing selected inhibitors in functional assays, including cell-based (C2C12 myotubes) assays and in vivo efficacy models of muscle wasting. The identification of clinical candidate inhibitors of MuRF-1 is the first step in the development of a class of novel targeted therapies for muscle wasting. These therapies should be efficacious in treating muscle wasting associated with aging, cancer, diabetes, and other chronic conditions. PUBLIC HEALTH RELEVANCE: Muscle atrophy (wasting), also known as myopathy, is a clinical complication of many diseases, e.g., cancer, AIDS, and diabetes, as well as a natural consequence of inactivity and aging; it significantly diminishes quality of life. Progenra has developed a screening assay to find inhibitors of an enzyme (called MuRF-1) that is associated with muscle protein degradation. Phase II work will consist of using this assay to find suitable inhibitors and making them drug-like by applying medicinal chemistry. In this supplemental project, the best of these inhibitors of MuRF-1 will be tested in cellular and animal models of muscle wasting as an initial step in their pre-clinical development; this will shorten the time it takes to move them into clinical trials. Ultimately, one of these compounds may advance to the clinic and market for the treatment of muscle wasting.