Developing a kinase inhibitor drug to treat spinal cord injury

摘要 脊髓损伤 (SCI) 是一种毁灭性的疾病，会造成终身后果，包括瘫痪。中环 神经系统 (CNS) 轴突通常无法再生，导致神经元连接不可逆转的丧失 以及受伤后的相关功能。目前估计 SCI 使国家医疗保健系统花费约 40.5 美元 每年十亿美元（CDC）。瘫痪者往往无法负担足够的医疗保险 涵盖相关的复杂的继发性或慢性疾病，这造成了巨大的经济负担 给他们及其家人带来心理上的痛苦。开发治疗 SCI 的药物将解决重大医疗保健问题 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 轴突生长：1）成人中枢神经系统神经元缺乏内在再生能力，2）外在抑制 面对受损轴突的微环境。尽管美国国立卫生研究院花费了数十年的研究和数十亿美元的资金， 目前尚无批准的促进轴突再生的药物。此外，药物的功效 发展可能受到以下事实的限制：每种机制仅针对两种生长抑制机制中的一种。 我们发现了第一个治疗候选药物，以小分子的形式，它可以同时 解决再生失败的两个根源。我们通过结合表型来实现这一点 筛选、基于目标的分析和机器学习来识别两者中的激酶目标 机制，外在的和内在的。然后我们鉴定了一个小分子（RO48），它表现出 多药理学特征与异常强劲的轴突生长促进相关。值得注意的是，RO48 表明 在多种 SCI 动物模型中具有高且可重复的疗效。我们进行了初步结构活动 对 RO48 的关系（SAR）研究有三个主要动机：1）SAR 和命中的初步调查 引导可行性，2) 提高 RO48 在细胞检测中的效力，以及 3) 生成新组合物 物质知识产权以允许药物开发。我们成功地展示了 SAR 和可行性，以及 产生新的知识产权（国际专利申请号 PCT/US18/58411，发明人：Al-Ali 等人）。初步在 体外和体内 DMPK/Tox 研究表明，迄今为止我们的化学工作已经消除了一些 RO48 的负债。在这个项目中，我们的目标是完成 SAR 研究并产生动物研究的四个主要候选者 测试。然后，我们将优先考虑一条线索，以推进一期临床试验。

ABSTRACT 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. 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.