Structural Basis of Colchicine-Site targeting Acylhydrazones active against Multidrug-Resistant Acute Lymphoblastic Leukemia

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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]}

Afiliação do(s) autor(es)

^[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

• Tipo de documento: Artigo Científico
• Fonte: ISCIENCE; v. 21, p. 95+, NOV 22 2019.
• Citações Web of Science: 0

Resumo

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)

• Processo FAPESP: 14/08247-8 - Estudos pré-clínicos de novos inibidores de DNA metiltransferase em leucemias agudas
• Beneficiário: Nathalia Moreno Cury
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 17/14737-6 - Estudo pré-clínico de um inibidor de tubulina que se liga no sítio de ligação a colchicina com potente atividade anti-leucêmica e baixa toxicidade
• Beneficiário: Nathalia Moreno Cury
• Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Doutorado