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
N1 - Funding Information:
N.M.C. was supported by a fellowship from Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP, 14/08247-8 , and 17/14737-6 ). J.A.Y. received a Productivity fellowship from the Brazilian National Counsel of Technological and Scientific Development ( CNPq 305896/2013-0 and 301596/2017-4 ). This work was supported in part by grants BFU2016-75319-R (AEI/FEDER, UE) (J.F.D.) from Ministerio de Economía y Competitividad . The crystal structure work was supported by grants from the Swiss National Science Foundation ( 31003A_166608 , to M.O.S.) and by the COST action CM1407 (to M.O.S.). Part of the in vivo work was supported by R01CA209829 and R01CA213912 , Hyundai Hope On Wheels Scholar Grant, Bear Necessities Pediatric Cancer Foundation , Alex’s Lemonade Stand Foundation , the Four Diamonds Fund of the Pennsylvania State University College of Medicine , and the John Wawrynovic Leukemia Research Scholar Endowment (to S.D.).
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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U2 - 10.1016/j.isci.2019.10.003
DO - 10.1016/j.isci.2019.10.003
M3 - Article
C2 - 31655259
AN - SCOPUS:85073606426
VL - 21
SP - 95
EP - 109
JO - iScience
JF - iScience
SN - 2589-0042
ER -