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

Research output: Contribution to journalArticle

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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Colchicine
Tubulin
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Tubulin Modulators
ATP-Binding Cassette Transporters
Therapeutic Uses
Leukemia
Binding Sites
Neoplasms

All Science Journal Classification (ASJC) codes

  • General

Cite this

Cury, N. M., Mühlethaler, T., Laranjeira, A. B. A., Canevarolo, R. R., Zenatti, P. P., Lucena-Agell, D., ... 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
Cury, Nathália Moreno ; Mühlethaler, Tobias ; Laranjeira, Angelo Brunelli Albertoni ; Canevarolo, Rafael Renatino ; Zenatti, Priscila Pini ; Lucena-Agell, Daniel ; Barasoain, Isabel ; Song, Chunhua ; Sun, Dongxiao ; Dovat, Sinisa ; Yunes, Rosendo Augusto ; Prota, Andrea Enrico ; Steinmetz, Michel Olivier ; Díaz, José Fernando ; Yunes, José Andrés. / Structural Basis of Colchicine-Site targeting Acylhydrazones active against Multidrug-Resistant Acute Lymphoblastic Leukemia. In: iScience. 2019 ; Vol. 21. pp. 95-109.
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Cury, NM, Mühlethaler, T, Laranjeira, ABA, Canevarolo, RR, Zenatti, PP, Lucena-Agell, D, Barasoain, I, Song, C, Sun, D, Dovat, S, Yunes, RA, Prota, AE, Steinmetz, MO, Díaz, JF & Yunes, JA 2019, 'Structural Basis of Colchicine-Site targeting Acylhydrazones active against Multidrug-Resistant Acute Lymphoblastic Leukemia', iScience, vol. 21, pp. 95-109. https://doi.org/10.1016/j.isci.2019.10.003

Structural Basis of Colchicine-Site targeting Acylhydrazones active against Multidrug-Resistant Acute Lymphoblastic Leukemia. / Cury, Nathália Moreno; Mühlethaler, Tobias; Laranjeira, Angelo Brunelli Albertoni; Canevarolo, Rafael Renatino; Zenatti, Priscila Pini; Lucena-Agell, Daniel; Barasoain, Isabel; Song, Chunhua; Sun, Dongxiao; Dovat, Sinisa; Yunes, Rosendo Augusto; Prota, Andrea Enrico; Steinmetz, Michel Olivier; Díaz, José Fernando; Yunes, José Andrés.

In: iScience, Vol. 21, 22.11.2019, p. 95-109.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Structural Basis of Colchicine-Site targeting Acylhydrazones active against Multidrug-Resistant Acute Lymphoblastic Leukemia

AU - Cury, Nathália Moreno

AU - Mühlethaler, Tobias

AU - Laranjeira, Angelo Brunelli Albertoni

AU - Canevarolo, Rafael Renatino

AU - Zenatti, Priscila Pini

AU - Lucena-Agell, Daniel

AU - Barasoain, Isabel

AU - Song, Chunhua

AU - Sun, Dongxiao

AU - Dovat, Sinisa

AU - Yunes, Rosendo Augusto

AU - Prota, Andrea Enrico

AU - Steinmetz, Michel Olivier

AU - Díaz, José Fernando

AU - Yunes, José Andrés

PY - 2019/11/22

Y1 - 2019/11/22

N2 - 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.

AB - 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.

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Cury NM, Mühlethaler T, Laranjeira ABA, Canevarolo RR, Zenatti PP, Lucena-Agell D et al. Structural Basis of Colchicine-Site targeting Acylhydrazones active against Multidrug-Resistant Acute Lymphoblastic Leukemia. iScience. 2019 Nov 22;21:95-109. https://doi.org/10.1016/j.isci.2019.10.003