Neuroprotective properties of c-Raf inhibitors

c-Raf 抑制剂的神经保护特性

• 批准号: 7228474
• 负责人: Santosh R D'Mello
• 金额: $ 29.5万
• 依托单位: UNIVERSITY OF TEXAS DALLAS
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7228474
• 关键词: 1-Phosphatidylinositol 3-Kinase; Affect; Animal Model; Apoptosis; Cessation of life; Chemicals; Clinical Treatment; Clinical Trials; Cultured Cells; Cytoplasmic Granules; Development; Dominant-Negative Mutation; Family Caregiver; Future; GW5074; Goals; Huntington Disease; In Vitro; JUN gene; Lead; MEKs; Mediating; Modification; Molecular; Molecular Target; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Neuroprotective Agents; Pathway interactions; Patients; Pharmaceutical Preparations; Property; Protein Overexpression; Quality of life; RPS6KA5 gene; Ras/Raf; Rattus; Role; SB 203580; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Signaling Molecule; Societies; Testing; Therapeutic; Therapeutic Agents; Therapeutic Intervention; Work; carbene; cost; in vivo; inhibitor/antagonist; nervous system disorder; neuron apoptosis; neuron loss; neuroprotection; novel; research study; small molecule; transcription factor

DESCRIPTION (provided by applicant): Neurological diseases disrupt the quality of the lives of patients, puts a tremendous burden on family caregivers, and cost society billions of dollars annually. A common feature of neurological diseases is the degeneration of neurons by apoptosis. Drugs that inhibit neuronal apoptosis could thus be candidates for therapeutic intervention in neurodegenerative disorders. Moreover, identifying the molecular targets of such neuroprotective drugs and understanding the signal transduction pathways that are utilized in their action would lead to the development of more effective therapeutic strategies. Working with a cell culture paradigm of neuronal apoptosis that uses rat cerebellar granule neurons we have identified a drug, GW5074 {5-Iodo-3-[(3,5-dibromo-4-hydroxyphenyl)methylene]-2-indolinone} that completely inhibits neuronal apoptosis. GW5074 is a specific and potent inhibitor of c-Raf when tested in vitro. Paradoxically, however, treatment of cultured neurons with GW5074 leads to the accumulation of activating modifications on c-Raf. Moreover, GW5074 treatment stimulates B-Raf activity. Among the molecules affected downstream of c-Raf in neurons treated with GW5074 are the antiapoptotic molecule NF-kappa b. GW5074 also inhibits the proapoptotic transcription factor, c-jun. Although GW5074 is the most effective, neuroprotection is also observed by two other chemical inhibitors of c-Raf. The utility of small molecule inhibitors of c-Raf as neuroprotective agents has not been described previously. The overall goal of this proposal is to use GW5074 to understand the molecular mechanism by which inhibitors of c-Raf exert their antiapoptotic effect and to more thoroughly investigate the potential of GW5074 as a neurotherapeutic agent. Our specific goals are to: (1) better understand the effect of GW5074 on c-Raf and B-Raf understand the effect of GW5074 on c-Raf, (2) analyze the downstream mechanisms by which GW5074 exerts its neuroprotective effect, and (3) examine whether the molecular effects of GW5074 in cultured cerebellar granule neurons are also observed in an animal model of neurodegeneration. It is our hope that GW5074 (or other c-Raf inhibitors like it) will emerge as a highly effective and versatile therapeutic agent that could proceed towards clinical trials for the treatment of neurological diseases in the near future.

描述(申请人提供)：神经系统疾病扰乱患者的生活质量，给家庭照顾者带来巨大负担，每年给社会造成数十亿美元的损失。神经性疾病的一个共同特征是神经元因细胞凋亡而退化。因此，抑制神经细胞凋亡的药物可能成为神经退行性疾病治疗干预的候选药物。此外，确定这类神经保护药物的分子靶点并了解其作用中使用的信号转导途径将有助于开发更有效的治疗策略。在使用大鼠小脑颗粒神经元的神经元凋亡细胞培养范例的工作中，我们已经确定了一种药物，GW5074{5-Iodo-3-[(3，5-dibromo-4-hydroxyphenyl)methylene]-2-indolinone}，它可以完全抑制神经元凋亡。体外实验表明，GW5074是c-Raf的特异性和强效抑制剂。然而，矛盾的是，GW5074处理培养的神经元导致c-Raf上激活修饰的积累。此外，GW5074处理可刺激B-Raf活性。在用GW5074处理的神经元中，受c-Raf下游影响的分子中有抗凋亡分子NF-kappab。GW5074还抑制促凋亡转录因子c-jun。虽然GW5074是最有效的，但c-Raf的另外两种化学抑制剂也观察到了神经保护作用。小分子c-Raf抑制剂作为神经保护剂的用途以前没有被描述过。本提案的总体目标是利用GW5074来了解c-Raf抑制剂发挥抗细胞凋亡作用的分子机制，并更深入地研究GW5074作为神经治疗剂的潜力。我们的具体目标是：(1)更好地了解GW5074对c-Raf和B-Raf的影响；(2)分析GW5074发挥神经保护作用的下游机制；(3)检测GW5074对培养的小脑颗粒神经元的分子作用是否也在神经退行性变的动物模型中观察到。我们希望GW5074(或其他类似的c-Raf抑制剂)将成为一种高效和多功能的治疗剂，有望在不久的将来进入治疗神经系统疾病的临床试验。