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: 8549070
• 负责人: Daniel Martin Watterson
• 金额: $ 90.28万
• 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/8549070
• 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; 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）：阿尔茨海默病（AD）是美国第六大死亡原因，但它是前十大疾病中唯一一种无法预防、治疗或减缓其进展的疾病。阿尔茨海默病导致的死亡人数超过了糖尿病、乳腺癌和前列腺癌的总和。我们假设阿尔茨海默氏症是一种进行性突触功能障碍，其中神经胶质-神经元轴是一个关键的参与者，并且在寻找疾病改善疗法的治疗发展范式中是可行的。神经元和神经胶质之间适当的交流和相互作用是大脑稳态的关键，而这些动态在疾病中受到干扰。靶向应激源诱导的神经胶质细胞和神经元的变化，有助于减轻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将是开发治疗方案的重要一步，增加了干预手段。