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：
8786965
负责人：
Steven I Reed
金额：
$ 43.39万
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/8786965
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 Functional disorder Gene Mutation Genes Genetic Models Goals 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 public health relevance 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）：帕金森氏病（PD）的特征是一系列运动障碍，这些疾病是导致多巴胺能神经元在中脑区域的渐进性死亡，称为黑质Nigra pars compacta（SNPC）。尽管每年在美国出现60,000例新的PD病例，并且估计有1000万人患有该疾病，但尚无已知的有效治疗方法，并且该疾病总是在进步。尽管大多数PD本质上都是零星的，但已显示出明显的队列是通过遗传传播的。通过研究引起PD的基因和突变，希望对分子水平的病因和病理学的理解将导致有效的疗法。在这种情况下，我们一直从事旨在了解帕金的作用，帕金是一种泛素连接酶，由最常见的基因pd 2。我们的研究得出的结论是，帕克蛋白的神经保护作用至少部分是通过靶向另一种泛素连接酶SCFFFBW7的底物结合适配器，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生存的Bcl-2家族成员Mcl-1，这对于神经元存活至关重要。使用硅方法，我们已经确定了SCFFFBW7的小分子抑制剂。所有这些都与FBW7结合，并防止其与原代神经元中的MCL-1形成生产性相互作用。最重要的是，这些化合物可保护原代神经元免受亚纳摩尔浓度下各种形式的应激诱导的凋亡。因此，我们建议使用具有良好药代动力学特性的一种化合物来确定FBW7是否是使用已建立的小鼠PD模型在体内有效的治疗靶标。如果这些实验成功，我们的最终目标是到达具有吸毒特征的FBW7抑制剂，以便可以将它们开发到进入人类临床试验的阶段。