Fbw7 as a therapeutic target for treating Parkinson's disease

描述（由申请人提供）：帕金森病（PD）以一系列运动障碍为特征，由中脑致密黑质（SNpc）区域多巴胺能神经元的进行性死亡引起。尽管美国每年有6万例PD新病例，全世界估计有1000万人患有PD，但目前还没有已知的有效治疗方法，而且这种疾病总是不断发展的。虽然大多数帕金森病在本质上是散发性的，但有一个重要的队列已被证明是遗传传播的。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和病理，从而找到有效的治疗方法。在这方面，我们一直致力于研究parkin的作用，这是一种由隐性遗传性帕金森病中最常突变的基因PARK2编码的泛素连接酶。我们的研究得出结论，帕金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点是促进存活的Bcl-2家族成员Mcl-1，对神经元存活至关重要。使用硅方法，我们已经确定了SCFFbw7的小分子抑制剂。所有这些都与Fbw7结合，并阻止其在初级神经元中与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保护初级神经元免受各种形式的应激诱导的凋亡。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，在已建立的小鼠PD模型中确定Fbw7是否是有效的体内治疗靶点。如果这些实验成功，我们的最终目标是获得具有类似药物特性的Fbw7抑制剂，以便它们可以发展到进入人体临床试验的阶段。

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.