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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

Structural Basis of Colchicine-Site targeting Acylhydrazones active against Multidrug-Resistant Acute Lymphoblastic Leukemia

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Author(s):
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Cury, Nathalia Moreno [1, 2] ; Muehlethaler, Tobias [3] ; Albertoni Laranjeira, Angelo Brunelli [2] ; Canevarolo, Rafael Renatino [2] ; Zenatti, Priscila Pini [2] ; Lucena-Agell, Daniel [4] ; Barasoain, Isabel [4] ; Song, Chunhua [5] ; Sun, Dongxiao [5] ; Dovat, Sinisa [5] ; Yunes, Rosendo Augusto [6] ; Prota, Andrea Enrico [3] ; Steinmetz, Michel Olivier [3, 7] ; Fernando Diaz, Jose [4] ; Yunes, Jose Andres [8, 2]
Total Authors: 15
Affiliation:
[1] Univ Estadual Campinas, Grad Program Genet & Mol Biol, BR-13083210 Campinas, SP - Brazil
[2] Ctr Infantil Boldrini, Lab Biol Mol, Rua Dr Gabriel Porto 1270, BR-13083210 Campinas, SP - Brazil
[3] Paul Scherrer Inst, Div Biol & Chem, Lab Biomol Res, CH-5232 Villigen - Switzerland
[4] CSIC, Ctr Invest Biol, E-28006 Madrid - Spain
[5] Penn State Univ, Dept Pediat, Coll Med, Hershey, PA 17033 - USA
[6] Univ Fed Santa Catarina, Dept Chem, BR-88040900 Florianopolis, SC - Brazil
[7] Univ Basel, Biozentrum, CH-4056 Basel - Switzerland
[8] Univ Estadual Campinas, Fac Med Sci, Genet Dept, BR-13083887 Campinas, SP - Brazil
Total Affiliations: 8
Document type: Journal article
Source: ISCIENCE; v. 21, p. 95+, NOV 22 2019.
Web of Science Citations: 0
Abstract

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 beta-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. (AU)

FAPESP's process: 14/08247-8 - Preclinical studies of novel inhibitors of DNA methyltransferase in acute leukemia
Grantee:Nathalia Moreno Cury
Support type: Scholarships in Brazil - Doctorate
FAPESP's process: 17/14737-6 - Preclinical study of a colchicine binding site tubulin inhibitor with potent anti-leukemia activity and low toxicity
Grantee:Nathalia Moreno Cury
Support type: Scholarships abroad - Research Internship - Doctorate