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

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

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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 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.

Original languageEnglish (US)
Pages (from-to)95-109
Number of pages15
JournaliScience
Volume21
DOIs
StatePublished - Nov 22 2019

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Cury, N. M., Mühlethaler, T., Laranjeira, A. B. A., Canevarolo, R. R., Zenatti, P. P., Lucena-Agell, D., Barasoain, I., Song, C., Sun, D., Dovat, S., Yunes, R. A., Prota, A. E., Steinmetz, M. O., Díaz, J. F., & Yunes, J. A. (2019). Structural Basis of Colchicine-Site targeting Acylhydrazones active against Multidrug-Resistant Acute Lymphoblastic Leukemia. iScience, 21, 95-109. https://doi.org/10.1016/j.isci.2019.10.003