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: 8422736
• 负责人: Daniel Martin Watterson
• 金额: $ 95.82万
• 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 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8422736
• 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; novel; phase 1 study; pre-clinical; preclinical evaluation; prevent; 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. PUBLIC HEALTH RELEVANCE: The recent National Alzheimer's Project Act (NAPA; Public Law 111-375) clearly defines the rapidly growing nature of the problem and requires a national plan in 2012. Campaigns initiated in 2013 will not reach a clear clinical outcome until 2020 or later, with reduction to standard clinical practice being post-2020 based on timeline precedents in drug development, clinical trial phases, and regulatory approval. The proposed campaign, if initiated within the coming year, falls well within this timeline and offers the potential for new molecular entity (NME) entry into the multi-drug arsenal needed to delay onset, slow progression, and treat existing AD across the long timeline of disease progression

描述(申请人提供)：阿尔茨海默病(AD)是美国第六大死亡原因，但它是前十名中唯一一种无法预防、治愈或减缓其进展的疾病。AD导致的死亡人数比糖尿病、乳腺癌和前列腺癌的总和还要多。我们假设AD是一种进行性突触功能障碍，其中胶质细胞-神经元轴是一个关键角色，在寻找疾病修改疗法方面作为一种治疗发展范例是可行的。神经元和神经胶质细胞之间的适当沟通和相互作用是大脑动态平衡的关键，而这些动态在疾病中受到干扰。靶向应激诱导的胶质细胞和神经元的变化有助于病理，提供了减缓疾病进展机制的潜力，这些机制存在于各种中枢神经系统疾病中。无论这种机制是直接致病机制，还是疾病易感性和发病的贡献者，这个过程的小分子调节器都将是发展治疗机制的重要一步，从而增加干预的武器装备。 这一建议的重点是应激相关蛋白激酶p38？MAPK，它是真核细胞信号转导通路中的一个关键节点，将应激信号放大并转换为生理变化。该激酶是多种疾病的既定药物发现靶点，但直到最近才成为中枢神经系统药物发现努力的重点。对p38？MAPK作为AD靶点的追求增加是由于一系列里程碑的结合，从人类中枢神经系统疾病中的激酶激活的证明，动物模型研究的结果，以及产生能够改善动物模型结果的中枢神经系统穿透性抑制剂的可行性的证明。 我们建议使用一种经过验证的药物发现引擎，该引擎成功地交付了新型CNS小分子药物候选药物，这些候选药物进展到了与该建议相同的IND目标，并经历了第一阶段的非人类研究，没有不良事件。本项目的具体目标是：目标1.优化第二代抑制剂MW01-10-181SRM，以便在保留靶标活性、选择性和体内功能的情况下改善非GLP admet相关特性，以便能够优先考虑单个候选者进行GLP Ind-Enabling评估。目的2.对一种同类最佳候选化合物进行GLP临床前评估，以产生IND。目的3.向FDA提交一种新的分子实体IND的申请，用于未来临床开发的第一阶段人类临床评估。 目前，没有批准的药物可以改变AD的病理进展，也没有选择性的p38？MAPK抑制剂药物在AD临床试验中(现有的临床前开发工作 主要集中在多激酶抑制剂)。因此，拟议的开发活动将解决该领域的科学空白，并有可能产生新的小分子候选对象，作为首个人类研究的交付成果。 与公共卫生相关：最近的《国家阿尔茨海默氏症项目法》(NAPA；公法111-375)明确界定了这一问题迅速增长的性质，并要求在2012年制定一项国家计划。2013年发起的活动要到2020年或更晚才能达到明确的临床结果，根据药物开发、临床试验阶段和监管批准的时间表先例，2020年后才能减少到标准临床实践。拟议的活动，如果在来年启动，完全符合这一时间表，并提供了新的分子实体(NME)进入所需的多种药物武器库所需的潜力，以延缓发病，减缓进展，并在疾病进展的长时间线上治疗现有的AD