Protein Kinase CK-1 Inhibitors As New Potential Drugs for Amyotrophic Lateral Sclerosis
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- 作者：Irene G. Salado ; Miriam Redondo ; Murilo L. Bello ; Concepci贸n Perez ; Nicole F. Liachko ; Brian C. Kraemer ; Laetitia Miguel ; Magalie Lecourtois ; Carmen Gil ; Ana Martinez ; Daniel I. Perez
- 刊名：Journal of Medicinal Chemistry
- 出版年：2014
- 出版时间：March 27, 2014
- 年：2014
- 卷：57
- 期：6
- 页码：2755-2772
- 全文大小：774K
- 年卷期：v.57,no.6(March 27, 2014)
- ISSN：1520-4804
文摘
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease where motor neurons in cortex, brain stem, and spinal cord die progressively, resulting in muscle wasting, paralysis, and death. Currently, effective therapies for ALS are lacking; however, identification of pathological TAR DNA-binding protein 43 (TDP-43) as the hallmark lesion in sporadic ALS suggests new therapeutic targets for pharmacological intervention. Pathological TDP-43 phosphorylation appears to drive the onset and progression of ALS and may result from upregulation of the protein kinase CK-1 in affected neurons, resulting in postranslational TDP-43 modification. Consequently, brain penetrant specific CK-1 inhibitors may provide a new therapeutic strategy for treating ALS and other TDP-43 proteinopathies. Using a chemical genetic approach, we report the discovery and further optimization of a number of potent CK-1未 inhibitors. Moreover, these small heterocyclic molecules are able to prevent TDP-43 phosphorylation in cell cultures, to increase Drosophila lifespan by reduction of TDP-43 neurotoxicity, and are predicted to cross the blood鈥揵rain barrier. Thus, N-(benzothiazolyl)-2-phenyl-acetamides are valuable drug candidates for further studies and may be a new therapeutic approach for ALS and others pathologies in which TDP-43 is involved.