Molecular Modeling Section (MMS), Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Via Marzolo 5, 35131, Padova, Italy.
Department of Chemical and Pharmaceutical Sciences, University of Trieste, Via Licio Giorgeri 1, 34127, Trieste, Italy.
ChemMedChem. 2018 Dec 20;13(24):2601-2605. doi: 10.1002/cmdc.201800632. Epub 2018 Nov 21.
Riluzole, approved by the US Food and Drug Administration (FDA) in 1995, is the most widespread oral treatment for the fatal neurodegenerative disorder amyotrophic lateral sclerosis (ALS). The drug, whose mechanism of action is still obscure, mitigates progression of the illness, but unfortunately with only limited improvements. Herein we report the first demonstration, using a combination of computational and in vitro studies, that riluzole is an ATP-competitive inhibitor of the protein kinase CK1 isoform δ, with an IC value of 16.1 μm. This allows us to rewrite its possible molecular mechanism of action in the treatment of ALS. The inhibition of CK1δ catalytic activity indeed links the two main pathological hallmarks of ALS: transactive response DNA-binding protein of 43 kDa (TDP-43) proteinopathy and glutamate excitotoxicity, exacerbated by the loss of expression of glial excitatory amino acid transporter-2 (EAAT2).
利鲁唑于 1995 年获得美国食品和药物管理局（FDA）批准，是治疗致命神经退行性疾病肌萎缩侧索硬化症（ALS）最广泛使用的口服治疗药物。该药的作用机制仍不清楚，但其能减缓疾病的进展，但不幸的是，仅有有限的改善。在此，我们首次通过计算和体外研究相结合的方法证明，利鲁唑是蛋白激酶 CK1 同工型 δ 的一种 ATP 竞争性抑制剂，IC 值为 16.1μm。这使我们能够重新书写其在治疗 ALS 中的可能分子作用机制。CK1δ 催化活性的抑制确实将 ALS 的两个主要病理标志联系起来：反式激活反应 DNA 结合蛋白 43kDa（TDP-43）蛋白病和谷氨酸兴奋性毒性，由胶质细胞兴奋性氨基酸转运蛋白-2（EAAT2）表达缺失加剧。
