| Full text | |
| Author(s): Show less - |
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 Opportunities: | 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 Opportunities: | Scholarships abroad - Research Internship - Doctorate |