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（由申请人提供）：阿尔茨海默氏病 (AD) 是美国第六大死因，但它是前 10 名疾病中唯一无法预防、治愈或减缓其进展的疾病。 AD 造成的死亡人数比糖尿病、乳腺癌和前列腺癌死亡人数的总和还多。我们假设 AD 是一种进行性突触功能障碍疾病，其中胶质神经元轴是关键参与者，并且可以作为寻找疾病缓解疗法的治疗开发范例。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稳态的关键，而这些动态在疾病中会受到干扰。针对应激源引起的神经胶质细胞和神经元的病理学变化，有可能减弱多种中枢神经系统疾病中存在的疾病进展机制。无论该机制是直接致病机制还是疾病易感性和发病的促成因素，该过程的小分子调节剂都将是开发治疗方案的重要一步，从而增加干预的武器库。 该提案的重点是应激相关蛋白激酶 p38¿ MAPK，它是真核细胞信号转导级联中的关键节点，可放大应激信号并将其转导为生理变化。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工作的焦点。人们越来越多地追求 p38¿ MAPK 作为 AD 靶点，这是由于一系列里程碑的结合，包括人类 CNS 疾病中激酶激活的证明、动物模型研究的结果，以及生成可以改善动物模型结果的 CNS 渗透抑制剂的可行性。 我们建议使用经过验证的药物发现引擎，该引擎成功交付了新型中枢神经系统小分子候选药物，该候选药物已达到与本提案相同的 IND 目标，并通过了首次非人类 1 期研究，没有出现任何不良事件。该项目的具体目标是： 目标 1. 优化第二代抑制剂 MW01-10-181SRM，以改善非 GLP ADMET 相关特性，同时保留目标活性、选择性和体内功能，以便单个候选药物可以优先用于 GLP IND 评估。目标 2. 对同类最佳候选化合物进行 GLP 临床前评估，以生成 IND。目标 3. 向 FDA 提交新分子实体 IND 申请，用于未来临床开发中的 1 期首次人体临床评估。 目前，尚无批准的改变 AD 病理进展的药物，也没有选择性 p38¿ MAPK 抑制剂药物处于 AD 临床试验中（现有的临床前开发工作 专注于多激酶抑制剂）。因此，拟议的开发活动将解决该领域的科学差距，并有可能产生新的小分子候选物，用于首次人体研究作为可交付成果。