Fbw7 as a therapeutic target for treating Parkinson's disease

Fbw7作为治疗帕金森病的治疗靶点

基本信息

批准号：
8850907
负责人：
Steven I Reed
金额：
$ 41.43万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-06-01 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8850907
关键词：
Acute Adverse effects Aging Apoptosis Apoptotic BCL2 gene Behavioral Binding Biological Assay Biological Availability Cell Death Cessation of life Characteristics Clinical Trials Collection Computer Simulation Coupled Disease Disease model Dissection Dose Etiology Exhibits FBXW7 gene Family member Gene Mutation Genes Genetic Models Goals Health Hour Human In Vitro Incidence Inherited Intoxication Lead Libraries Life Link Long-Term Effects Longevity Mediating Midbrain structure Modeling Molecular Motor Mus Mutate Nature Nerve Degeneration Nerve Fibers Neurons Oncogene Proteins Oral PARK2 gene Parkinson Disease Pathology Penetrance Property RNA Interference Relative (related person)Research Risk Role Sampling Staging Stress Substantia nigra structure Syndrome Technology Testing Therapeutic Time Toxic effect Ubiquitin Ubiquitin-mediated Proteolysis Pathway Veins Western Blotting Work cancer risk carcinogenesis cohort cost dopaminergic neuron drug discovery effective therapy in vivo inhibitor/antagonist motor disorder mouse model neuromelanin neuron loss neuronal survival parkin gene/protein pars compacta pharmacokinetic characteristic prevent research study response screening small molecule therapeutic target therapy development tumorigenesis ubiquitin ligase

项目摘要

DESCRIPTION (provided by applicant): Parkinson's disease (PD) is characterized by a spectrum of motor disorders that is caused be progressive death of dopaminergic neurons in a midbrain region known as the substantia nigra pars compacta (SNpc). Although 60,000 new cases of PD present in the US every year and an estimated 10 million people are living with the disease world-wide, there is no known effective treatment and the disease is invariably progressive. Although most PD is sporadic in nature, a significant cohort has been shown to be transmitted genetically. By investigating the genes and mutations that cause PD, it has been hoped that an understanding of the etiology and pathology of the disease at the molecular level will lead to effective therapies. In that vein, we have been engaged in research aimed at understanding the role of parkin, a ubiquitin ligase encoded by the most frequently mutated gene in recessive hereditary PD, PARK2. Our research has led to the conclusion that the neuroprotective effect of parkin is mediated, at least in part, by targeting the substrate binding adaptor of another ubiquitin ligase, SCFFbw7, for ubiquitin-mediated proteasomal degradation. We have also determined that the critical target of the SCFFbw7 ubiquitin ligase in this context is the pro-survival Bcl-2 family member Mcl-1, essential for neuronal survival. Using an in silico approach, we have identified small molecule inhibitors of SCFFbw7. All bind to Fbw7 and prevent it from forming productive interactions with Mcl-1 in primary neurons. Most importantly, these compounds protect primary neurons from various forms of stress-induced apoptosis at sub-nanomolar concentrations. Therefore, we are proposing to use one compound with good pharmacokinetic characteristics to determine whether Fbw7 is a valid therapeutic target in vivo using established mouse PD models. Should these experiments be successful, our ultimate goal is to arrive at Fbw7 inhibitors that have druglike characteristics so that they can be developed to the stage of entering human clinical trials.

描述（由申请人提供）：帕金森病（PD）的特征是一系列运动障碍，其由称为黑质致密部（SNpc）的中脑区域多巴胺能神经元进行性死亡引起。尽管美国每年出现 60,000 例新的帕金森病病例，并且全世界估计有 1000 万人患有这种疾病，但目前还没有已知的有效治疗方法，而且这种疾病总是在进展。尽管大多数帕金森病本质上是散发性的，但有一个重要群体已被证明是通过遗传传播的。通过研究导致帕金森病的基因和突变，人们希望在分子水平上了解该疾病的病因学和病理学将带来有效的治疗方法。本着这一精神，我们一直致力于了解 Parkin 的作用，parkin 是一种泛素连接酶，由隐性遗传性 PD 中最常见的突变基因 PARK2 编码。我们的研究得出这样的结论：parkin 的神经保护作用至少部分是通过靶向另一种泛素连接酶 SCFFbw7 的底物结合接头来介导的，用于泛素介导的蛋白酶体降解。我们还确定，在这种情况下，SCFFbw7 泛素连接酶的关键靶标是促存活的 Bcl-2 家族成员 Mcl-1，它对于神经元的存活至关重要。使用计算机方法，我们已经鉴定出 SCFFbw7 的小分子抑制剂。所有这些都与 Fbw7 结合，并阻止其与初级神经元中的 Mcl-1 形成有效的相互作用。最重要的是，这些化合物在亚纳摩尔浓度下可以保护原代神经元免受各种形式的应激诱导的细胞凋亡。因此，我们建议使用一种具有良好药代动力学特征的化合物，通过已建立的小鼠 PD 模型来确定 Fbw7 是否是体内有效的治疗靶点。如果这些实验成功，我们的最终目标是获得具有药物特性的Fbw7抑制剂，以便将其开发到进入人体临床试验阶段。