Developing a kinase inhibitor drug to treat spinal cord injury

开发治疗脊髓损伤的激酶抑制剂药物

• 批准号: 10785727
• 负责人: Hassan Al-Ali
• 金额: $ 7.66万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-04 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10785727
• 关键词: Address; Adult; Affect; Animal Model; Animal Testing; Award; Axon; Biological Assay; Cells; Central Nervous System; Chemistry; Chronic; Complex; Dendrites; Development; Drug Targeting; Economic Burden; Effectiveness; Environment; FDA approved; Failure; Family; Future; Generations; Goals; Growth; Health Insurance; Healthcare; Healthcare Systems; In Vitro; Injury; International; Intraventricular Infusion; Investigation; Lead; Legal patent; Machine Learning; Microinjections; Molecular; Motivation; Natural regeneration; Neurites; Neurons; Orphan; Paralysed; Parents; Persons; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase I Clinical Trials; Phenotype; Phosphotransferases; Property; Recovery; Recovery of Function; Regenerative capacity; Regenerative response; Regression Analysis; Reproducibility; Research; Role; Series; Signal Pathway; Signal Transduction; Site; Source; Spinal cord injury; Stroke; Structure-Activity Relationship; Testing; Therapeutic; Traumatic Brain Injury; United States National Institutes of Health; Weight; analog; axon growth; axon injury; axon regeneration; central nervous system injury; clinical application; clinical candidate; clinical development; cost; drug development; improved; in vivo; inhibitor; inhibitor therapy; kinase inhibitor; lead candidate; mouse model; neuron loss; neuronal cell body; phosphoproteomics; programs; protein kinase C gamma; psychologic; regeneration following injury; repaired; screening; small molecule; synergism; therapeutic candidate

ABSTRACT (from parent award) Spinal cord injury (SCI) is a devastating condition with life-long consequences that include paralysis. Central nervous system (CNS) axons typically fail to regenerate, leading to irreversible losses of neuronal connectivity and associated functions after injury. Despite being an orphan indication, SCI is now estimated to cost the nation's healthcare system around $40.5 billion annually (CDC). People living with paralysis are often unable to afford health insurance that adequately covers the associated complex secondary or chronic conditions, which places tremendous economic burden and psychological suffering on them and their families. Developing a drug to treat SCI will address major healthcare and societal needs. Encouraging axon regeneration in the CNS is challenged by at least two separate mechanisms that suppress axonal growth: 1) a lack of intrinsic regenerative capacity in adult CNS neurons, and 2) the extrinsic inhibitory microenvironment confronting damaged axons. Despite decades of research and billions of NIH dollars spent, there are still no approved drugs for promoting axon regeneration. Moreover, the effectiveness of drugs in development is likely limited by the fact that each targets only one of the two growth-suppressive mechanisms. We have discovered the first therapeutic candidate, in the form of a small molecule, which can simultaneously address both sources of regeneration failure. We accomplished this using a combination of phenotypic screening, target-based profiling, and machine learning to identify kinase targets within each of the two mechanisms, extrinsic and intrinsic. We then identified a single small molecule (RO48) that manifests a polypharmacology profile correlated with unusually robust promotion of axon growth. Remarkably, RO48 showed high and reproducible efficacy in multiple animal models of SCI. We performed preliminary structure activity relationship (SAR) studies on RO48 with three main motivations: 1) preliminary investigation of the SAR and hit- to-lead feasibility, 2) improving the potency of RO48 in cell-based assays, and 3) generation of new composition of matter IP to permit drug development. We were successful in demonstrating SAR and feasibility, as well as generating new IP (International Patent Application No. PCT/US18/58411, inventors: Al-Ali et al.). Preliminary in vitro and in vivo DMPK/Tox studies revealed that our chemistry efforts thus far have already eliminated several liabilities of RO48. In this project, we aim to finalize the SAR studies and generate four lead candidates for animal testing. We will then prioritize one lead to advance towards a Phase I clinical trial.

摘要（来自父母奖） 脊髓损伤（SCI）是一种毁灭性的疾病，其终身后果包括麻痹。中央 神经系统（CNS）轴突通常无法再生，导致神经元连通性的不可逆转损失 以及受伤后相关的功能。尽管是孤儿，但SCI现在估计要花费 国家的医疗保健系统每年约405亿美元（CDC）。瘫痪的人通常无法 提供适当涵盖相关复杂次要或慢性状况的健康保险，这些保险 给他们及其家人带来巨大的经济负担和心理苦难。开发药物 治疗SCI将满足主要的医疗保健和社会需求。 在CNS中鼓励轴突再生受到至少两种抑制的单独机制的挑战 轴突生长：1）成人CNS神经元缺乏内在再生能力，2）外部抑制作用 微环境面对受损的轴突。尽管经过数十年的研究和数十亿美元的花费，但 仍然没有批准的药物来促进轴突再生。此外，药物的有效性 发展可能受到以下事实的限制：每个事实仅针对两种增长抑制机制之一。 我们以小分子的形式发现了第一个治疗候选者 解决两个再生故障来源。我们使用表型的组合完成了此操作 筛选，基于目标的分析和机器学习，以识别两者中每个中的每一个中的激酶目标 机制，外在和内在。然后，我们确定了一个表现出A的单个小分子（RO48） 多药理学谱与轴突生长的异常促进相关。值得注意的是，RO48显示 在多种SCI动物模型中，高且可再现的功效。我们进行了初步结构活动 关于RO48的关系（SAR）研究与三个主要动机：1）对SAR和HIT-的初步研究 可行性，2）提高基于细胞的测定中RO48的效力，3）新成分的产生 物质IP允许药物开发。我们成功地展示了SAR和可行性， 生成新的IP（国际专利申请号PCT/US18/58411，发明者：Al-Ali等人）。初步 体外和体内DMPK/TOX研究表明，到目前为止，我们的化学工作已经消除了几个 RO48的负债。在这个项目中，我们旨在最终确定SAR研究并为动物生成四个主要候选者 测试。然后，我们将优先考虑一个铅，以迈向I期临床试验。