Dual leucine zipper kinase (DLK), expressed primarily in neuronal cells, is a regulator of neuronal degeneration in response to cellular stress from chronic disease or neuronal injury. This makes it an attractive target for the treatment of neurodegenerative diseases such as Alzheimer’s, Parkinson’s, and amyotrophic lateral sclerosis, and neuronal injury, such as chemotherapy-induced peripheral neuropathy. Here, we describe the discovery of a potent, selective, brain-penetrant DLK inhibitor, KAI-11101 (59). Throughout the program’s progression, medicinal chemistry challenges such as potency, hERG inhibition, CNS penetration, CYP3A time-dependent inhibition, and kinase selectivity were overcome through the implementation of cutting-edge in silico tools. KAI-11101 displayed an excellent in vitro safety profile and showed neuroprotective properties in an ex vivo axon fragmentation assay as well as dose-dependent activity in a mouse PD model.

中文翻译：

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计算机模拟技术促成了 KAI-11101 的发现，KAI-11101 是一种用于治疗神经退行性疾病和神经元损伤的临床前 DLK 抑制剂


双亮氨酸拉链激酶 （DLK） 主要在神经元细胞中表达，是响应慢性疾病或神经元损伤引起的细胞应激而引起的神经元变性的调节因子。这使其成为治疗神经退行性疾病（如阿尔茨海默病、帕金森病和肌萎缩侧索硬化症）和神经元损伤（如化疗引起的周围神经病变）的有吸引力的靶点。在这里，我们描述了一种有效的、选择性的、可透过脑的 DLK 抑制剂 KAI-11101 的发现 （59）。在整个项目进展过程中，通过实施尖端的计算机分析工具，克服了药用化学挑战，如效力、hERG 抑制、CNS 渗透、CYP3A 时间依赖性抑制和激酶选择性。KAI-11101 显示出优异的体外安全性，并在离体轴突碎裂测定中显示出神经保护特性，在小鼠 PD 模型中显示出剂量依赖性活性。