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Título: | Targeting nuclear protein TDP-43 by cell division cycle kinase 7 inhibitors: A new therapeutic approach for amyotrophic lateral sclerosis |
Autor: | Rojas-Prats, Elisa CSIC ORCID; Martínez-González, Loreto CSIC ORCID ; Gonzalo-Consuegra, Claudia; Liachko, Nicole F.; Pérez, Concepción CSIC ORCID; Ramírez, David; Kraemer, Brian C.; Martín-Requero, Ángeles CSIC ORCID ; Pérez, Daniel I. CSIC ORCID; Gil, Carmen CSIC ORCID ; De Lago, E.; Martínez Gil, Ana CSIC ORCID | Palabras clave: | CDC7 inhibitors TDP-43 ALS FTLD Drug discovery |
Fecha de publicación: | 15-ene-2021 | Editor: | Elsevier | Citación: | European Journal of Medicinal Chemistry 210:112968 ( 2021) | Resumen: | Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with no known cure. Aggregates of the nuclear protein TDP-43 have been recognized as a hallmark of proteinopathy in both familial and sporadic cases of ALS. Post-translational modifications of this protein, include hyperphosphorylation, cause disruption of TDP-43 homeostasis and as a consequence, promotion of its neurotoxicity. Among the kinases involved in these changes, cell division cycle kinase 7 (CDC7) plays an important role by directly phosphorylating TDP-43. In the present manuscript the discovery, synthesis, and optimization of a new family of selective and ATP-competitive CDC7 inhibitors based on 6-mercaptopurine scaffold are described. Moreover, we demonstrate the ability of these inhibitors to reduce TDP-43 phosphorylation in both cell cultures and transgenic animal models such as C. elegans and Prp-hTDP43 (A315T) mice. Altogether, the compounds described here may be useful as versatile tools to explore the role of CDC7 in TDP-43 phosphorylation and also as new drug candidates for the future development of ALS therapies. | Descripción: | 58 p.-11 fig.-2 tab. | Versión del editor: | https://doi.org/10.1016/j.ejmech.2020.112968 | URI: | http://hdl.handle.net/10261/228072 | DOI: | 10.1016/j.ejmech.2020.112968 | ISSN: | 0223-5234 |
Aparece en las colecciones: | (CIB) Artículos |
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