Development of MAP4 Kinase Inhibitors as Motor Neuron-Protecting Agents
Development of MAP4 Kinase Inhibitors as Motor Neuron-Protecting Agents
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DOI：
10.1016/j.chembiol.2019.10.005
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发表时间：
2019-12-19
影响因子：
8.6
通讯作者：
Stockwell, Brent R.
中科院分区：
文献类型：
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作者：
Bos, Pieter H.;Lowry, Emily R.;Stockwell, Brent R.
许多神经退行性疾病中的致病突变会导致蛋白质病，从而引发内质网 (ER) 应激。然而，对于患有这些疾病的患者来说，几乎没有治疗选择。使用体外筛选平台来鉴定保护人类运动神经元免受内质网应激介导的变性的化合物，我们发现针对丝裂原激活蛋白激酶激酶激酶 (MAP4K) 家族的化合物具有神经保护作用。激酶抑制剂 URMC-099（化合物 1）脱颖而出，成为有希望进一步优化的先导化合物。我们将基于结构的化合物设计与经受 ER 应激的神经元的功能活性测试相结合，开发了一系列具有改善的 MAP4K 抑制作用并同时提高效力和功效的类似物。进行了进一步的结构修饰以增强化合物1衍生物的药代动力学特征。 Prostetin/12k 是一种极其有效、代谢稳定且能穿透血脑屏障的化合物，非常适合未来在神经退行性疾病动物模型中进行测试。
Disease-causing mutations in many neurodegenerative disorders lead to proteinopathies that trigger endoplasmic reticulum(ER) stress. However, few therapeutic options exist for patients with these diseases. Using an in vitro screening platform to identify compounds that protect human motor neurons from ER stress-mediated degeneration, we discovered that compounds targeting the mitogen-activated protein kinase kinase kinase kinase (MAP4K) family are neuroprotective. The kinase inhibitor URMC-099 (compound 1) stood out as a promising lead compound for further optimization. We coupled structure-based compound design with functional activity testing in neurons subjected to ER stress to develop a series of analogs with improved MAP4K inhibition and concomitant increases in potency and efficacy. Further structural modifications were performed to enhance the pharmacokinetic profiles of the compound 1 derivatives. Prostetin/12k emerged as an exceptionally potent, metabolically stable, and blood-brain barrier-penetrant compound that is well suited for future testing in animal models of neurodegeneration.