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      Protein Kinase CK-1 Inhibitors As New Potential Drugs for Amyotrophic Lateral Sclerosis

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          Abstract

          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.

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          Most cited references 20

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          Optimization of parameters for semiempirical methods V: Modification of NDDO approximations and application to 70 elements

          Several modifications that have been made to the NDDO core-core interaction term and to the method of parameter optimization are described. These changes have resulted in a more complete parameter optimization, called PM6, which has, in turn, allowed 70 elements to be parameterized. The average unsigned error (AUE) between calculated and reference heats of formation for 4,492 species was 8.0 kcal mol−1. For the subset of 1,373 compounds involving only the elements H, C, N, O, F, P, S, Cl, and Br, the PM6 AUE was 4.4 kcal mol−1. The equivalent AUE for other methods were: RM1: 5.0, B3LYP 6–31G*: 5.2, PM5: 5.7, PM3: 6.3, HF 6–31G*: 7.4, and AM1: 10.0 kcal mol−1. Several long-standing faults in AM1 and PM3 have been corrected and significant improvements have been made in the prediction of geometries. Figure Calculated structure of the complex ion [Ta6Cl12]2+ (footnote): Reference value in parenthesis Electronic supplementary material The online version of this article (doi:10.1007/s00894-007-0233-4) contains supplementary material, which is available to authorized users.
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            Ligand docking and binding site analysis with PyMOL and Autodock/Vina

            Docking of small molecule compounds into the binding site of a receptor and estimating the binding affinity of the complex is an important part of the structure-based drug design process. For a thorough understanding of the structural principles that determine the strength of a protein/ligand complex both, an accurate and fast docking protocol and the ability to visualize binding geometries and interactions are mandatory. Here we present an interface between the popular molecular graphics system PyMOL and the molecular docking suites Autodock and Vina and demonstrate how the combination of docking and visualization can aid structure-based drug design efforts.
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              TDP-43 mutant transgenic mice develop features of ALS and frontotemporal lobar degeneration.

              Frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) are neurodegenerative diseases that show considerable clinical and pathologic overlap, with no effective treatments available. Mutations in the RNA binding protein TDP-43 were recently identified in patients with familial amyotrophic lateral sclerosis (ALS), and TDP-43 aggregates are found in both ALS and FTLD-U (FTLD with ubiquitin aggregates), suggesting a common underlying mechanism. We report that mice expressing a mutant form of human TDP-43 develop a progressive and fatal neurodegenerative disease reminiscent of both ALS and FTLD-U. Despite universal transgene expression throughout the nervous system, pathologic aggregates of ubiquitinated proteins accumulate only in specific neuronal populations, including layer 5 pyramidal neurons in frontal cortex, as well as spinal motor neurons, recapitulating the phenomenon of selective vulnerability seen in patients with FTLD-U and ALS. Surprisingly, cytoplasmic TDP-43 aggregates are not present, and hence are not required for TDP-43-induced neurodegeneration. These results indicate that the cellular and molecular substrates for selective vulnerability in FTLD-U and ALS are shared between mice and humans, and suggest that altered DNA/RNA-binding protein function, rather than toxic aggregation, is central to TDP-43-related neurodegeneration.
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                Author and article information

                Journal
                J Med Chem
                J. Med. Chem
                jm
                jmcmar
                Journal of Medicinal Chemistry
                American Chemical Society
                0022-2623
                1520-4804
                04 March 2015
                04 March 2014
                27 March 2014
                : 57
                : 6
                : 2755-2772
                Affiliations
                []Instituto de Química Médica, CSIC , Juan de la Cierva 3, 28006 Madrid, Spain
                []Faculdade de Farmácia, Universidade Federal do Rio de Janeiro , 21949-900 Rio de Janeiro, Brazil
                [§ ]Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System , Seattle, Washington 98108, United States
                []Department of Medicine, Gerontology Division, University of Washington , Seattle, Washington 98104, United States
                []Department of Psychiatry and Behavioral Sciences, University of Washington , Seattle, Washington 98195, United States
                [# ]Inserm, U1079 , 76183 Rouen, France
                []IRIB Institute for Research and Innovation in Biomedicine, Normandie Univ (University of Rouen) , 76183 Rouen, France
                Author notes
                [* ]For A.M.: phone, + 34 91 5622900; fax, + 34 915644862; E-mail, amartinez@ 123456iqm.csic.es .
                [* ]For D.I.P.: phone, + 34 91 5622900; fax, + 34 915644862; E-mail, dperez@ 123456iqm.csic.es .
                Article
                10.1021/jm500065f
                3969104
                24592867
                Copyright © 2014 American Chemical Society
                Funding
                National Institutes of Health, United States
                Categories
                Article
                Custom metadata
                jm500065f
                jm-2014-00065f

                Pharmaceutical chemistry

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