Identification of therapeutic compounds for Charcot-Marie-Tooth disease type 1E/1

1E/1 型腓骨肌萎缩症治疗化合物的鉴定

• 批准号: 8684419
• 负责人: Pragna Patel
• 金额: $ 44.37万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8684419
• 关键词: Autophagocytosis; Biological Assay; Cell membrane; Cell surface; Cells; Charcot-Marie-Tooth Disease; DNA; Disease; Drug Kinetics; Drug toxicity; Evaluation; Event; Goals; Heat shock proteins; Human; Lead; Leg; Membrane; Mus; Mutation; Myelin Proteins; Myelin Sheath; Nerve; Neuropathy; Operative Surgical Procedures; Palliative Surgery; Pathway interactions; Patients; Peripheral; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phenotype; Physical Rehabilitation; Point Mutation; Process; Property; Proteins; Quality of life; Recruitment Activity; Regimen; Rehabilitation therapy; Resolution; Schwann Cells; Signal Transduction; Site; Structure-Activity Relationship; Testing; Therapeutic; Toxic effect; Ursidae Family; analog; arm; base; compound 30; dysmyelination; effective therapy; hereditary neuropathy; high throughput screening; in vivo; mouse model; mutant; protein transport; public health relevance; scaffold; small molecule; trafficking

DESCRIPTION (provided by applicant): Charcot-Marie-Tooth disease is the most common inherited neuropathy in humans. There are no effective treatments for any form of CMT other than palliative surgery and physical rehabilitation. The neuropathy can significantly lower the quality of life in patients. We co-discovered the unprecedented large DNA duplication underlying CMT1A, an autosomal dominant subtype seen in ~60% of all CMT patients. Overproduction of the peripheral myelin protein, PMP22 underlies CMT1A while ~5% of CMT1 patients classified as having CMT1E bear a dominant point mutation in PMP22. Examination of mice over-expressing Pmp22 or bearing a Pmp22 point mutation have shown that excessive or defective Pmp22 accumulates in cytosolic or perinuclear aggregates. This is thought to decrease the amount of PMP22 protein within the Schwann cell membrane and likely contribute to the dysmyelinating phenotype. Additionally, there is evidence that point mutations in Pmp22 lower the efficiency by which the wild-type protein traffics to the cell surface. We hypothesize that a small molecule that stimulates degradation or resolution of the aggregates and possibly allows proper folding/processing of the PMP22 could have therapeutic benefit. To test this hypothesis, we have developed a high-throughput screening (HTS) assay to identify small-molecules that reduce aggregation of PMP22 bearing a point mutation. Results obtained from an initial screen of 30,000 compounds has identified 30 compounds that that reduce aggregate formation by >70%. Towards identification of a diverse set of lead compounds that can be developed as therapeutic regimens for CMT1E/1A, we propose the following Aims: (1) Examine the most active compounds after resynthesis from each of the scaffolds identified by our initial screen the effect on aggregates, their site of action, trafficking of PMP22 to the membrane and toxicity to delineate the most promising compounds. (2) Conduct medicinal chemistry driven optimization of the hit compounds and test new analogs in the primary and secondary assays and build structure-activity relationships (SAR). The goal is to identify analogs with appropriate potency, low toxicity, drug-like properties and pharmacokinetics that are suitable for in vivo evaluation in mouse models of CMT1E and CMT1A. The deliverables from Aims 1 and 2 are at least two compounds with efficacy at levels <1uM and toxicity at levels >50uM that would be ready for testing in mouse models of CMT1E and CMT1A.

描述（由申请人提供）：腓骨肌萎缩症是人类最常见的遗传性神经病。除了姑息手术和身体康复外，没有任何形式的CMT的有效治疗方法。神经病变可显著降低患者的生活质量。我们共同发现了CMT 1A潜在的前所未有的大DNA重复，CMT 1A是一种常染色体显性亚型，见于约60%的CMT患者。外周髓磷脂蛋白PMP 22的过度产生是CMT 1A的基础，而约5%的CMT 1患者被归类为CMT 1 E，在PMP 22中携带显性点突变。对过表达Pmp 22或携带Pmp 22点突变的小鼠的检查表明，过量或缺陷的Pmp 22在胞质或核周聚集体中积累。这被认为减少了许旺细胞膜内PMP 22蛋白的量，并可能导致髓鞘形成障碍表型。此外，有证据表明Pmp 22中的点突变降低了野生型蛋白质运输到细胞表面的效率。我们假设刺激聚集体降解或分解并可能允许PMP 22适当折叠/加工的小分子可能具有治疗益处。为了验证这一假设，我们开发了一种高通量筛选（HTS）试验，以确定减少携带点突变的PMP 22聚集的小分子。从30，000种化合物的初始筛选获得的结果已经鉴定出30种化合物，其使聚集体形成减少> 70%。为了鉴定可以作为CMT 1 E/1A治疗方案开发的一组不同的先导化合物，我们提出了以下目的：（1）检查通过我们的初步筛选鉴定的每个支架再合成后最具活性的化合物对聚集体的影响、它们的作用位点、PMP 22向膜的运输和毒性，以描绘最有希望的化合物。(2)对目标化合物进行药物化学驱动的优化，并在一级和二级试验中测试新的类似物，并建立构效关系（SAR）。目的是鉴定具有适当效力、低毒性、药物样性质和药代动力学的类似物，其适合于在体内评价， CMT 1 E和CMT 1A小鼠模型。目标1和2的可交付成果是至少两种化合物，其效力水平为<1uM and toxicity at levels >50 μ M，可用于CMT 1 E和CMT 1A小鼠模型的测试。