6F7C

TUBULIN-Compound 12 complex

Summary for 6F7C

• Entry DOI: 10.2210/pdb6f7c/pdb
• Descriptor: Tubulin alpha-1B chain, 2-(N-MORPHOLINO)-ETHANESULFONIC ACID, PHOSPHOMETHYLPHOSPHONIC ACID ADENYLATE ESTER, ... (12 entities in total)
• Functional Keywords: cell cycle, tubulin fold, cytoskeleton, microtubule
• Biological source: Rattus norvegicus (Rat); More
• Total number of polymer chains: 6
• Total formula weight: 264870.68

Authors

Muehlethaler, T.,Prota, A.E.,Steinmetz, M.O. (deposition date: 2017-12-08, release date: 2018-12-19, Last modification date: 2024-01-17)

Primary citation

Cury, N.M.,Muhlethaler, 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.,Diaz, J.F.,Yunes, J.A.
Structural Basis of Colchicine-Site targeting Acylhydrazones active against Multidrug-Resistant Acute Lymphoblastic Leukemia.
Iscience, 21:95-109, 2019

PubMed 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.

PubMed: 31655259
DOI: 10.1016/j.isci.2019.10.003

Experimental method

X-RAY DIFFRACTION (2.002 Å)