| Autor: |
Nathália Moreno Cury, Tobias Mühlethaler, Angelo Brunelli Albertoni Laranjeira, Rafael Renatino Canevarolo, Priscila Pini Zenatti, Daniel Lucena-Agell, Isabel Barasoain, Chunhua Song, Dongxiao Sun, Sinisa Dovat, Rosendo Augusto Yunes, Andrea Enrico Prota, Michel Olivier Steinmetz, José Fernando Díaz, José Andrés Yunes |
| Jazyk: |
angličtina |
| Rok vydání: |
2019 |
| Předmět: |
|
| Zdroj: |
iScience, Vol 21, Iss , Pp 95-109 (2019) |
| Druh dokumentu: |
article |
| ISSN: |
2589-0042 |
| DOI: |
10.1016/j.isci.2019.10.003 |
| Popis: |
Summary: 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. : Drugs; Biological Sciences; Molecular Biology; Structural Biology; Cancer Subject Areas: Drugs, Biological Sciences, Molecular Biology, Structural Biology, Cancer |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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