Developing a kinase inhibitor drug to treat spinal cord injury

摘要(来自家长奖) 脊髓损伤(SCI)是一种破坏性的疾病，其终生后果包括瘫痪。中环 神经系统(CNS)轴突通常不能再生，导致神经元连接的不可逆转的损失 以及损伤后的相关功能。尽管脊髓损伤是一个孤立的症状，但据估计，现在 美国的医疗体系每年约为405亿美元(CDC)。生活在瘫痪中的人通常无法 提供适当覆盖相关复杂的继发性或慢性病的健康保险， 给他们及其家人带来巨大的经济负担和心理痛苦。开发一种药物 治疗脊髓损伤将解决主要的医疗保健和社会需求。 鼓励中枢神经系统轴突再生受到至少两种独立机制的挑战，这些机制抑制了 轴突生长：1)成年中枢神经系统神经元缺乏内在再生能力，2)外源性抑制 面对受损轴突的微环境。尽管进行了数十年的研究，花费了NIH数十亿美元， 目前还没有被批准的促进轴突再生的药物。此外，药物在治疗中的有效性 发展可能受到这样一个事实的限制，即每个国家都只针对两种抑制增长的机制中的一种。 我们已经发现了第一种治疗候选药物，以小分子的形式，它可以同时 解决再生故障的两个来源。我们使用表型组合实现了这一点 筛选、基于靶标的分析和机器学习以识别两者中的每一个中的激酶靶标 机制，外在和内在的。然后我们鉴定了一个小分子(RO48)，它表现出一种 多元药理学特征与异常强劲的促进轴突生长相关。值得注意的是，RO48显示 在多种脊髓损伤动物模型中的高效率和可重复性。我们进行了初步的结构活动 RO48的关系(SAR)研究有三个主要动机：1)对SAR和HIT的初步调查- 领先的可行性，2)提高RO48在基于细胞的分析中的效力，以及3)新成分的产生 物质知识产权，以允许药物开发。我们成功地论证了SAR和可行性，以及 生成新的知识产权(国际专利申请号PCT/US18/58411，发明人：al-Ali等人)。初步入站 体外和体内的DMPK/Tox研究表明，到目前为止，我们的化学努力已经消除了几个 RO48的负债。在这个项目中，我们的目标是完成特区的研究，并产生四个主要的动物候选人 测试。然后，我们将优先选择一条线索，以推进I期临床试验。

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.