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Development of MAP4 Kinase Inhibitors as Motor Neuron-Protecting Agents.
Cell Chemical Biology ( IF 6.6 ) Pub Date : 2019-10-31 , DOI: 10.1016/j.chembiol.2019.10.005
Pieter H Bos 1 , Emily R Lowry 2 , Jonathon Costa 2 , Sebastian Thams 2 , Alejandro Garcia-Diaz 3 , Arie Zask 1 , Hynek Wichterle 4 , Brent R Stockwell 5
Affiliation  

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.

中文翻译:

MAP4激酶抑制剂作为运动神经元保护剂的开发。

在许多神经退行性疾病中,引起疾病的突变会导致引起内质网(ER)应激的蛋白病。但是,对于患有这些疾病的患者,几乎没有治疗选择。使用体外筛选平台来识别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,我们发现靶向有丝分裂原激活的蛋白激酶激酶激酶激酶(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)作为进一步优化的有前途的先导化合物脱颖而出。我们将基于结构的化合物设计与功能活性测试相结合,对处于ER应激状态的神经元进行了研究,以开发出一系列具有改善的MAP4K抑制作用并同时提高了效能和功效的类似物。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作为一种异常有效,代谢稳定和血脑屏障渗透性化合物出现,非常适合将来在神经退行性动物模型中进行测试。
更新日期:2019-11-09
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