PDBsum entry 6f7c

Cell cycle

PDB id: 6f7c

Contents

Protein chains

431 a.a.

424 a.a.

118 a.a.

281 a.a.

Ligands

GTP ×2

GDP ×2

CVT

MES

ACP

Metals

_CA ×3

_MG ×5

Waters ×713

References listed in PDB file

Key reference

• Title: Structural basis of colchicine-Site targeting acylhydrazones active against multidrug-Resistant acute lymphoblastic leukemia.
• Authors: N.M.Cury, T.Mühlethaler, A.B.A.Laranjeira, R.R.Canevarolo, P.P.Zenatti, D.Lucena-Agell, I.Barasoain, C.Song, D.Sun, S.Dovat, R.A.Yunes, A.E.Prota, M.O.Steinmetz, J.F.Díaz, J.A.Yunes.
• Ref.: iScience, 2019, 21, 95. [DOI no: 10.1016/j.isci.2019.10.003]
• PubMed id: 31655259

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.