Structural Basis of Colchicine-Site targeting Acylhydrazones active against Multidrug-Resistant Acute Lymphoblastic Leukemia
| Autor: | Isabel Barasoain, Nathalia Moreno Cury, José Andrés Yunes, Andrea E. Prota, Dongxiao Sun, Chunhua Song, Priscila Pini Zenatti, Tobias Mühlethaler, Sinisa Dovat, Angelo Brunelli Albertoni Laranjeira, Daniel Lucena-Agell, Rosendo A. Yunes, Michel O. Steinmetz, Rafael Renatino Canevarolo, José Fernando Díaz |
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| Přispěvatelé: | Fundação de Amparo à Pesquisa do Estado de São Paulo, Conselho Nacional de Desenvolvimento Científico e Tecnológico (Brasil), Ministerio de Economía y Competitividad (España), Swiss National Science Foundation, University of Pennsylvania, Cury, Nathália Moreno [0000-0002-1749-812X], Zenatti, Priscila Pini [0000-0002-8662-7458], Lucena-Agell, Daniel [0000-0001-7198-2900], Barasoain, Isabel [0000-0003-2013-085X], Song, Chunhua [0000-0001-7563-0339], Dovat, Sinisa [0000-0003-3906-6165], Yunes, Rosendo Augusto [0000-0002-4529-5733], Prota, Andrea E. [0000-0003-0875-5339], Steinmetz, Michel O. [0000-0001-6157-3687], Díaz, José Fernando [0000-0003-2743-3319], Cury, Nathália Moreno, Zenatti, Priscila Pini, Lucena-Agell, Daniel, Barasoain, Isabel, Song, Chunhua, Dovat, Sinisa, Yunes, Rosendo Augusto, Prota, Andrea E., Steinmetz, Michel O., Díaz, José Fernando |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
ATP-binding cassette transporter 02 engineering and technology macromolecular substances Pharmacology Article 03 medical and health sciences chemistry.chemical_compound Structural Biology medicine Colchicine lcsh:Science Molecular Biology Cancer Multidisciplinary biology Therapeutic effect Drugs Cell cycle Biological Sciences 021001 nanoscience & nanotechnology medicine.disease 3. Good health Multiple drug resistance Biological sciences 030104 developmental biology Tubulin chemistry Mechanism of action biology.protein lcsh:Q medicine.symptom 0210 nano-technology |
| Zdroj: | iScience iScience, Vol 21, Iss, Pp 95-109 (2019) Digital.CSIC. Repositorio Institucional del CSIC instname |
| ISSN: | 2589-0042 |
| 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. Graphical Abstract Highlights • 3,4,5-trimethoxy-N-acylhydrazones bind to the colchicine site of tubulin • 12 forms a single H-bond with αThr179 and causes steric hindrance of tubulin βT7 loop • 3,4,5-trimethoxy-N-acylhydrazones feature low toxicity • 12 shows therapeutic effect against multidrug-resistant acute lymphoblastic leukemia Drugs; Biological Sciences; Molecular Biology; Structural Biology; Cancer |
| Databáze: | OpenAIRE |
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