piroxicam and Amyotrophic-Lateral-Sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease without any effective treatment. Protein TDP-43 is a pathological hallmark of ALS in both sporadic and familiar patients. Post-translational modifications of TDP-43 promote its aggregation in the cytoplasm. Tau-Tubulin kinase (TTBK1) phosphorylates TDP-43 in cellular and animal models; thus, TTBK1 inhibitors emerge as a promising therapeutic strategy for ALS. The design, synthesis, biological evaluation, kinase-ligand complex structure determination, and molecular modeling studies confirmed novel pyrrolopyrimidine derivatives as valuable inhibitors for further development. Moreover, compound

Topics: Amyotrophic Lateral Sclerosis; Animals; Brain; Case-Control Studies; DNA-Binding Proteins; Humans; Inflammation; Macrophages; Male; Mice; Mice, Inbred BALB C; Mice, Transgenic; Phosphorylation; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Rats; Rats, Wistar; Spinal Cord; Tissue Distribution

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-1δ 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-brain 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.

Topics: Amyotrophic Lateral Sclerosis; Animals; Animals, Genetically Modified; Benzothiazoles; Blood-Brain Barrier; Casein Kinase I; Cell Membrane Permeability; Cells, Cultured; DNA-Binding Proteins; Drosophila; Drug Design; Drug Discovery; HEK293 Cells; Heterocyclic Compounds; High-Throughput Screening Assays; Humans; Magnetic Resonance Spectroscopy; Models, Molecular; Molecular Conformation; Neurons; Neurotoxicity Syndromes; Phosphorylation; Protein Kinase Inhibitors; Substrate Specificity