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dc.contributor.authorRojas-Prats, Elisa
dc.contributor.authorMartínez-González, Loreto
dc.contributor.authorGonzalo-Consuegra, Claudia
dc.contributor.authorLiachko, Nicole F.
dc.contributor.authorPérez, Concepción
dc.contributor.authorRamírez, David
dc.contributor.authorKraemer, Brian C.
dc.contributor.authorMartín-Requero, Ángeles
dc.contributor.authorPerez, Daniel I.
dc.contributor.authorGil, Carmen
dc.contributor.authorDe Lago, Eva
dc.contributor.authorMartínez, Ana
dc.date.accessioned2020-11-17T17:31:32Z
dc.date.available2020-11-17T17:31:32Z
dc.date.issued2020-10-28
dc.identifier10.1016/j.ejmech.2020.112968
dc.identifier.issn02235234
dc.identifier.urihttps://hdl.handle.net/20.500.12728/7190
dc.description.abstractAmyotrophic 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.isoenes_ES
dc.publisherElsevier Masson s.r.l.es_ES
dc.subjectALSes_ES
dc.subjectCDC7 inhibitorses_ES
dc.subjectDrug discoveryes_ES
dc.subjectFTLDes_ES
dc.subjectTDP-43es_ES
dc.titleTargeting nuclear protein TDP-43 by cell division cycle kinase 7 inhibitors: A new therapeutic approach for amyotrophic lateral sclerosises_ES
dc.typeArticlees_ES


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