Developing a kinase inhibitor drug to treat spinal cord injury

摘要 脊髓损伤（SCI）是一种具有终身后果的破坏性疾病，包括瘫痪。中央 神经系统（CNS）轴突通常不能再生，导致神经元连接的不可逆损失 以及损伤后的相关功能。SCI现在估计花费国家医疗保健系统约40.5美元 每年10亿美元（CDC）。瘫痪患者通常无法负担足够的医疗保险， 涵盖了相关的复杂的继发性或慢性疾病，这些疾病造成了巨大的经济负担， 对他们及其家人造成心理伤害。开发治疗SCI的药物将解决主要的医疗保健问题 和社会需求。 在中枢神经系统中促进轴突再生受到至少两种不同机制的挑战， 轴突生长：1）成年CNS神经元缺乏内在的再生能力，2）外在的抑制性生长。 微环境面对受损的轴突。尽管数十年的研究和数十亿美元的国家卫生研究院花费， 仍然没有批准的药物用于促进轴突再生。此外，药物在 发展可能受到以下事实的限制，即每种药物仅靶向两种生长抑制机制中的一种。 我们已经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来源。我们通过结合表型 筛选、基于靶点的分析和机器学习，以识别两种蛋白质中的激酶靶点。 机制，外在的和内在的。然后，我们确定了一个单一的小分子（RO 48）， 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，RO 48显示 在SCI的多种动物模型中具有高的和可重复的功效。我们进行了初步的结构活动， 关系（SAR）研究RO 48有三个主要动机：1）SAR和命中的初步调查- 以引导可行性，2）在基于细胞的测定中提高RO 48的效力，和3）产生新的组合物 允许药物开发。我们成功地证明了SAR和可行性，以及 产生新的IP（国际专利申请号PCT/US 18/58411，发明人：Al-Ali等）。初步的 体外和体内DMPK/Tox研究表明，我们的化学努力迄今已经消除了几个 RO 48的责任在这个项目中，我们的目标是完成SAR研究，并产生四个主要候选动物， 试验.然后，我们将优先考虑一个线索，以推进I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.