Biological and Pharmacological Characterization of Benzothiazole-Based CK-1δ Inhibitors in Models of Parkinson's Disease.
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ABSTRACT:
SUBMITTER: Morales-Garcia JA
PROVIDER: S-EPMC6044573 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundTar DNA binding protein 43 (TDP-43) hyperphosphorylation, caused by Casein kinase 1 (CK-1) protein isoforms, is associated with the onset and progression of Amyotrophic Lateral Sclerosis (ALS). Among the reported isoforms and splice variants of CK-1 protein superfamily, CK-1δ is known to phosphorylate different serine and threonine sites on TDP-43 protein in vitro and thus qualifies as a potential target for ALS treatment.ResultsThe developed GQSAR (group based quantitative structure activity relationship) model displayed satisfactory statistical parameters for the dataset of experimentally reported N-Benzothiazolyl-2-Phenyl Acetamide derivatives. A combinatorial library of molecules was also generated and the activities were predicted using the statistically sound GQSAR model. Compounds with higher predicted inhibitory activity were screened against CK-1δ that resulted in to the potential novel leads for CK-1δ inhibition.ConclusionsIn this study, a robust fragment based QSAR model was developed on a congeneric set of experimentally reported molecules and using combinatorial library approach, a series of molecules were generated from which we report two top scoring, CK-1δ inhibitors i.e., CHC (6-benzyl-2-cyclopropyl-4-{[(4-cyclopropyl-6-ethyl-1,3-benzothiazol-2-yl)carbamoyl]methyl}j-3-fluorophenyl hydrogen carbonate) and DHC (6-benzyl-4-{[(4-cyclopropyl-6-ethyl-1,3-benzothiazol-2-yl)carbamoyl]methyl}-2-(decahydronaphthalen-1-yl)-3-hydroxyphenyl hydrogen carbonate) with binding energy of -6.11 and -6.01 kcal/mol, respectively.
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Project description:Pathogenesis of amyotrophic lateral sclerosis (ALS), a devastating disease where no treatment exists, involves the compartmentalization of the nuclear protein TDP-43 (TAR DNA-binding protein 43) in the cytoplasm which is promoted by its aberrant phosphorylation and others posttranslational modifications. Recently, it was reported that CK-1δ (protein casein kinase-1δ) is able to phosphorylate TDP-43. Here, the preclinical efficacy of a benzothiazole-based CK-1δ inhibitor IGS-2.7, both in a TDP-43 (A315T) transgenic mouse and in a human cell-based model of ALS, is shown. Treatment with IGS-2.7 produces a significant preservation of motor neurons in the anterior horn at lumbar level, a decrease in both astroglial and microglial reactivity in this area, and in TDP-43 phosphorylation in spinal cord samples. Furthermore, the recovery of TDP-43 homeostasis (phosphorylation and localization) in a human-based cell model from ALS patients after treatment with IGS-2.7 is also reported. Moreover, we have shown a trend to increase in CK-1δ mRNA in spinal cord and significantly in frontal cortex of sALS cases. All these data show for the first time the in vivo modulation of TDP-43 toxicity by CK-1δ inhibition with IGS-2.7, which may explain the benefits in the preservation of spinal motor neurons and point to the relevance of CK-1δ inhibitors in a future disease-modifying treatment for ALS.
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