Preclinical Alzheimers Disease Drug Development of Novel MAPK Inhibitors

新型 MAPK 抑制剂的临床前阿尔茨海默病药物开发

• 批准号: 8724322
• 负责人: Daniel Martin Watterson
• 金额: $ 114.17万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-30 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8724322
• 关键词: Academia; Address; Adverse event; Alzheimer' s Disease; Animal Model; Animals; Attenuated; Biological; Biology; Brain; Cause of Death; Central Nervous System Diseases; Clinical; Clinical Trials; Communication; Data; Development; Diabetes Mellitus; Disease; Disease Outcome; Disease Progression; Disease susceptibility; Epidemic; Eukaryotic Cell; Evaluation; Functional disorder; Future; Gene Expression; Generations; Goals; Homeostasis; Human; Industry; Intervention; KRP protein; Laws; MAP Kinase Gene; MAPK14 gene; Malignant neoplasm of prostate; Mitogen-Activated Protein Kinase Inhibitor; Molecular; Molecular Target; Nature; Neurodegenerative Disorders; Neuroglia; Neurological outcome; Neurons; Onset of illness; Outcome; Pathology; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Phosphotransferases; Physiological; Process; Property; Protein-Serine-Threonine Kinases; Signal Transduction; Stress; Synapses; Therapeutic; TimeLine; United States; base; clinical practice; cytokine; design; drug candidate; drug development; drug discovery; falls; improved; in vivo; inhibitor/antagonist; killings; kinase inhibitor; malignant breast neoplasm; mitogen-activated protein kinase p38; novel; phase 1 study; pre-clinical; preclinical evaluation; prevent; public health relevance; research clinical testing; small molecule; stressor; therapeutic development

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is the sixth-leading cause of death in the United States, yet it is the only disease among the top 10 without a way to prevent, cure or slow its progression. AD kills more people than diabetes or breast cancer and prostate cancer combined. We hypothesize that AD is a progressive synaptic dysfunction disorder in which the glia-neuron axis is a key player and viable as a therapeutic development paradigm in the search for disease-modifying therapeutics. Appropriate communication and interactions between neurons and glia are key to brain homeostasis, and these dynamics are perturbed in disease. Targeting stressor-induced changes in both glia and neurons that contribute to pathology offers the potential to attenuate disease progression mechanisms present in a diverse array of CNS disorders. Regardless of whether the mechanism is a direct causative one or a contributor to disease susceptibility and onset, small molecule modulators of the process would be a major step in development of therapeutic regimes that add to the armamentarium for intervention. This proposal is focused on the stress-related protein kinase p38¿ MAPK, a key node in the signal transduction cascades of eukaryotic cells that amplify and transduce stress signals into physiological changes. The kinase is an established drug discovery target for diverse disorders, but only recently has become the focus of CNS drug discovery efforts. The increased pursuit of p38¿ MAPK as an AD target is due to a combination of landmarks, ranging from the demonstration of kinase activation in human CNS diseases, outcomes from animal model studies, and the demonstration of feasibility for generating CNS-penetrant inhibitors that can improve outcomes in animal models. We propose to use a validated drug discovery engine that successfully delivered novel CNS small molecule drug candidates that progressed to the same IND goal as this proposal and went through first-inhuman phase 1 studies with no adverse events. The specific aims for this project are: Aim 1. Optimize a second-generation inhibitor, MW01-10-181SRM, in order to improve non-GLP ADMET-related properties with retention of target activity, selectivity and in vivo function such that a single candidate can be prioritized for GLP IND-enabling evaluation. Aim 2. Perform GLP preclinical evaluation of a best-in-class candidate compound in order to generate an IND. Aim 3. Submit application for a new molecular entity IND to the FDA for phase 1 first-in-human clinical evaluation in future clinical development. Currently, there are no approved drugs that alter AD pathology progression, and no selective p38¿ MAPK inhibitor drugs in AD clinical trials (existing preclinical development efforts are focused on multi-kinase inhibitors). Therefore, the proposed development campaign will address scientific gaps in the field, and has the potential to yield novel small molecule candidates for first-in-human studies as deliverables.

描述（由适用提供）：阿尔茨海默氏病（AD）是美国第六个领先的死亡原因，但它是前十名中唯一的疾病，没有预防，治愈或减缓其进展的方法。 AD杀死的人数比糖尿病或乳腺癌和前列腺癌的杀死更多。我们假设AD是一种进行性突触功能障碍障碍，其中神经胶质神经元轴是关键人物，并且可以作为治疗性发育范式可行，以寻求调整疾病的治疗。神经元和神经胶质之间的适当沟通和相互作用是大脑稳态的关键，并且这些动态在疾病中受到干扰。靶向应激源引起的胶质元变化和神经元的变化有助于病理学，这可能会减弱在一系列中枢神经系统疾病中存在的疾病进展机制。无论该机制是直接灾难性的一种还是导致疾病易感性和发作的促进者，该过程的小分子调节剂将是治疗方案开发的主要步骤，这增加了为干预措施增加的治疗方案。 该建议集中在与应力相关的蛋白激酶p38 p38 p38 p38上，这是真核细胞信号转导级联中的一个关键节点，它将应力信号放大并将其转换为物理变化。激酶是潜水员疾病的既定药物发现靶标，但直到最近才成为CNS药物发现工作的重点。对p38？MAPK作为AD目标的追求增加是由于地标的组合，包括人类中枢神经系统疾病中激酶激活的演示，动物模型研究的结果，以及产生CNS-PENETR抑制剂的可行性，可以改善动物模型中的疾病。 我们建议使用经过验证的药物发现引擎，该引擎成功地传递了新型的CNS小分子候选者，该药物候选者与该提案相同，并经过了第一阶段的第一阶段研究，没有不良事件。该项目的具体目的是：AIM 1。优化第二代抑制剂MW01-10-181SRM，以改善非GLP ADMET相关的特性，并保留目标活动，选择性和体内功能，以便可以优先考虑单个候选者的GLP配置评估。 AIM 2。对一流的候选化合物进行GLP临床前评估，以生成IND。 AIM 3。向FDA提交新分子实体的申请，以在未来临床开发中进行第一阶段人类临床评估。 目前，没有批准的药物改变AD病理的进展，并且在AD临床试验中没有选择性p38？MAPK抑制剂药物（现有的临床前开发工作） 专注于多激酶抑制剂）。因此，拟议的开发运动将解决该领域的科学差距，并有潜力将新型的小分子候选者作为人类研究作为可交付成果。