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 language | English (US) |
|---|---|
| Pages (from-to) | 95-109 |
| Number of pages | 15 |
| Journal | iScience |
| Volume | 21 |
| DOIs | |
| State | Published - Nov 22 2019 |
Fingerprint
All Science Journal Classification (ASJC) codes
- General
Cite this
}
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 journal › Article
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.
UR - http://www.scopus.com/inward/record.url?scp=85073606426&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85073606426&partnerID=8YFLogxK
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 -