Por favor, use este identificador para citar o enlazar a este item:
http://hdl.handle.net/10261/196704
COMPARTIR / EXPORTAR:
SHARE CORE BASE | |
Visualizar otros formatos: MARC | Dublin Core | RDF | ORE | MODS | METS | DIDL | DATACITE | |
Título: | Structural basis of colchicine-site targeting acylhydrazones active against multidrug-resistant acute lymphoblastic leukemia |
Autor: | Cury, Nathália Moreno; Mühlethaler, Tobias; Laranjeira, Angelo Brunelli Albertoni; Canevarolo, Rafael Renatino; Zenatti, Priscila Pini; Lucena-Agell, Daniel CSIC ORCID ; Barasoain, Isabel CSIC ; Song, Chunhua; Sun,Dongxiao; Dovat, Sinisa; Yunes, Rosendo Augusto; Prota, Andrea E.; Steinmetz, Michel O.; Díaz, José Fernando CSIC ORCID ; Yunes, José Andrés | Palabras clave: | Biological sciences Cancer Drugs Molecular biology Structural Biology |
Fecha de publicación: | 22-nov-2019 | Editor: | Elsevier | Citación: | iScience 21:95-109 (2019) | Resumen: | Tubulin is one of the best validated anti-cancer targets, but most anti-tubulin agents have unfavorable therapeutic indexes. Here, we characterized the tubulin-binding activity, the mechanism of action, and the in vivo anti-leukemia efficacy of three 3,4,5-trimethoxy-N-acylhydrazones. We show that all compounds target the colchicine-binding site of tubulin and that none is a substrate of ABC transporters. The crystal structure of the tubulin-bound N-(1'-naphthyl)-3,4,5-trimethoxybenzohydrazide (12) revealed steric hindrance on the T7 loop movement of β-tubulin, thereby rendering tubulin assembly incompetent. Using dose escalation and short-term repeated dose studies, we further report that this compound class is well tolerated to >100 mg/kg in mice. We finally observed that intraperitoneally administered compound 12 significantly prolonged the overall survival of mice transplanted with both sensitive and multidrug-resistant acute lymphoblastic leukemia (ALL) cells. Taken together, this work describes promising colchicine-site-targeting tubulin inhibitors featuring favorable therapeutic effects against ALL and multidrug-resistant cells. | Descripción: | 38 p.-8 fig.-2 tab.-8 fig supl.-2 tab. supl. | Versión del editor: | https://doi.org/10.1016/j.isci.2019.10.003 | URI: | http://hdl.handle.net/10261/196704 | DOI: | 10.1016/j.isci.2019.10.003 | E-ISSN: | 2589-0042 |
Aparece en las colecciones: | (CIB) Artículos |
Ficheros en este ítem:
Fichero | Descripción | Tamaño | Formato | |
---|---|---|---|---|
iscience_Cury_2019.pdf | Artículo principal | 5,5 MB | Adobe PDF | Visualizar/Abrir |
CORE Recommender
PubMed Central
Citations
2
checked on 08-abr-2024
SCOPUSTM
Citations
4
checked on 24-abr-2024
WEB OF SCIENCETM
Citations
4
checked on 22-feb-2024
Page view(s)
212
checked on 23-abr-2024
Download(s)
101
checked on 23-abr-2024