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Targeting nuclear protein TDP-43 by cell division cycle kinase 7 inhibitors: A new therapeutic approach for amyotrophic lateral sclerosis
dc.contributor.author | Rojas-Prats, Elisa | |
dc.contributor.author | Martínez-González, Loreto | |
dc.contributor.author | Gonzalo-Consuegra, Claudia | |
dc.contributor.author | Liachko, Nicole F. | |
dc.contributor.author | Pérez, Concepción | |
dc.contributor.author | Ramírez, David | |
dc.contributor.author | Kraemer, Brian C. | |
dc.contributor.author | Martín-Requero, Ángeles | |
dc.contributor.author | Perez, Daniel I. | |
dc.contributor.author | Gil, Carmen | |
dc.contributor.author | De Lago, Eva | |
dc.contributor.author | Martínez, Ana | |
dc.date.accessioned | 2020-11-17T17:31:32Z | |
dc.date.available | 2020-11-17T17:31:32Z | |
dc.date.issued | 2020-10-28 | |
dc.identifier | 10.1016/j.ejmech.2020.112968 | |
dc.identifier.issn | 02235234 | |
dc.identifier.uri | https://hdl.handle.net/20.500.12728/7190 | |
dc.description.abstract | 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. | es_ES |
dc.language.iso | en | es_ES |
dc.publisher | Elsevier Masson s.r.l. | es_ES |
dc.subject | ALS | es_ES |
dc.subject | CDC7 inhibitors | es_ES |
dc.subject | Drug discovery | es_ES |
dc.subject | FTLD | es_ES |
dc.subject | TDP-43 | es_ES |
dc.title | Targeting nuclear protein TDP-43 by cell division cycle kinase 7 inhibitors: A new therapeutic approach for amyotrophic lateral sclerosis | es_ES |
dc.type | Article | es_ES |