دورية أكاديمية
Structural Basis of Colchicine-Site targeting Acylhydrazones active against Multidrug-Resistant Acute Lymphoblastic Leukemia.
العنوان: | Structural Basis of Colchicine-Site targeting Acylhydrazones active against Multidrug-Resistant Acute Lymphoblastic Leukemia. |
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المؤلفون: | Cury NM; Laboratório de Biologia Molecular, Centro Infantil Boldrini, Rua Dr. Gabriel Porto 1270, Campinas 13083-210, Brazil; Graduate Program in Genetics and Molecular Biology, State University of Campinas, Campinas 13083-210, Brazil., Mühlethaler T; Laboratory of Biomolecular Research, Division of Biology and Chemistry, Paul Scherrer Institut, 5232 Villigen PSI, Switzerland., Laranjeira ABA; Laboratório de Biologia Molecular, Centro Infantil Boldrini, Rua Dr. Gabriel Porto 1270, Campinas 13083-210, Brazil., Canevarolo RR; Laboratório de Biologia Molecular, Centro Infantil Boldrini, Rua Dr. Gabriel Porto 1270, Campinas 13083-210, Brazil., Zenatti PP; Laboratório de Biologia Molecular, Centro Infantil Boldrini, Rua Dr. Gabriel Porto 1270, Campinas 13083-210, Brazil., Lucena-Agell D; Centro de Investigaciones Biológicas, CSIC, 28006 Madrid, Spain., Barasoain I; Centro de Investigaciones Biológicas, CSIC, 28006 Madrid, Spain., Song C; Pennsylvania State University College of Medicine, Department of Pediatrics, Hershey, PA 17033, USA., Sun D; Pennsylvania State University College of Medicine, Department of Pediatrics, Hershey, PA 17033, USA., Dovat S; Pennsylvania State University College of Medicine, Department of Pediatrics, Hershey, PA 17033, USA., Yunes RA; Department of Chemistry, Federal University of Santa Catarina, Florianópolis 88040-900, Brazil., Prota AE; Laboratory of Biomolecular Research, Division of Biology and Chemistry, Paul Scherrer Institut, 5232 Villigen PSI, Switzerland., Steinmetz MO; Laboratory of Biomolecular Research, Division of Biology and Chemistry, Paul Scherrer Institut, 5232 Villigen PSI, Switzerland; University of Basel, Biozentrum, 4056 Basel, Switzerland., Díaz JF; Centro de Investigaciones Biológicas, CSIC, 28006 Madrid, Spain., Yunes JA; Laboratório de Biologia Molecular, Centro Infantil Boldrini, Rua Dr. Gabriel Porto 1270, Campinas 13083-210, Brazil; Genetics Department, Faculty of Medical Sciences, State University of Campinas, Campinas 13083-887, Brazil. Electronic address: andres@boldrini.org.br. |
المصدر: | IScience [iScience] 2019 Nov 22; Vol. 21, pp. 95-109. Date of Electronic Publication: 2019 Oct 02. |
نوع المنشور: | Journal Article |
اللغة: | English |
بيانات الدورية: | Publisher: Cell Press Country of Publication: United States NLM ID: 101724038 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2589-0042 (Electronic) Linking ISSN: 25890042 NLM ISO Abbreviation: iScience Subsets: PubMed not MEDLINE |
أسماء مطبوعة: | Original Publication: [Cambridge, MA] : Cell Press, [2018]- |
مستخلص: | 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. (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.) |
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معلومات مُعتمدة: | R01 CA209829 United States CA NCI NIH HHS; R01 CA213912 United States CA NCI NIH HHS |
فهرسة مساهمة: | Keywords: Biological Sciences; Cancer; Drugs; Molecular Biology; Structural Biology |
تواريخ الأحداث: | Date Created: 20191027 Latest Revision: 20200928 |
رمز التحديث: | 20221213 |
مُعرف محوري في PubMed: | PMC6820235 |
DOI: | 10.1016/j.isci.2019.10.003 |
PMID: | 31655259 |
قاعدة البيانات: | MEDLINE |
تدمد: | 2589-0042 |
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DOI: | 10.1016/j.isci.2019.10.003 |