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Biological Characterization of an Improved Pyrrole-Based Colchicine Site Agent Identified through Structure-Based Design.
Rohena, Cristina C; Telang, Nakul S; Da, Chenxiao; Risinger, April L; Sikorski, James A; Kellogg, Glen E; Gupton, John T; Mooberry, Susan L.
Afiliação
  • Rohena CC; Department of Pharmacology and Cancer Therapy & Research Center, University of Texas Health Science Center at San Antonio, San Antonio, Texas (C.C.R., A.L.R., S.L.M.); Department of Chemistry University of Richmond, Richmond Virginia (N.T., J.T.G.); Department of Medicinal Chemistry and Institut
  • Telang NS; Department of Pharmacology and Cancer Therapy & Research Center, University of Texas Health Science Center at San Antonio, San Antonio, Texas (C.C.R., A.L.R., S.L.M.); Department of Chemistry University of Richmond, Richmond Virginia (N.T., J.T.G.); Department of Medicinal Chemistry and Institut
  • Da C; Department of Pharmacology and Cancer Therapy & Research Center, University of Texas Health Science Center at San Antonio, San Antonio, Texas (C.C.R., A.L.R., S.L.M.); Department of Chemistry University of Richmond, Richmond Virginia (N.T., J.T.G.); Department of Medicinal Chemistry and Institut
  • Risinger AL; Department of Pharmacology and Cancer Therapy & Research Center, University of Texas Health Science Center at San Antonio, San Antonio, Texas (C.C.R., A.L.R., S.L.M.); Department of Chemistry University of Richmond, Richmond Virginia (N.T., J.T.G.); Department of Medicinal Chemistry and Institut
  • Sikorski JA; Department of Pharmacology and Cancer Therapy & Research Center, University of Texas Health Science Center at San Antonio, San Antonio, Texas (C.C.R., A.L.R., S.L.M.); Department of Chemistry University of Richmond, Richmond Virginia (N.T., J.T.G.); Department of Medicinal Chemistry and Institut
  • Kellogg GE; Department of Pharmacology and Cancer Therapy & Research Center, University of Texas Health Science Center at San Antonio, San Antonio, Texas (C.C.R., A.L.R., S.L.M.); Department of Chemistry University of Richmond, Richmond Virginia (N.T., J.T.G.); Department of Medicinal Chemistry and Institut
  • Gupton JT; Department of Pharmacology and Cancer Therapy & Research Center, University of Texas Health Science Center at San Antonio, San Antonio, Texas (C.C.R., A.L.R., S.L.M.); Department of Chemistry University of Richmond, Richmond Virginia (N.T., J.T.G.); Department of Medicinal Chemistry and Institut
  • Mooberry SL; Department of Pharmacology and Cancer Therapy & Research Center, University of Texas Health Science Center at San Antonio, San Antonio, Texas (C.C.R., A.L.R., S.L.M.); Department of Chemistry University of Richmond, Richmond Virginia (N.T., J.T.G.); Department of Medicinal Chemistry and Institut
Mol Pharmacol ; 89(2): 287-96, 2016 Feb.
Article em En | MEDLINE | ID: mdl-26655304
ABSTRACT
A refined model of the colchicine site on tubulin was used to design an improved analog of the pyrrole parent compound, JG-03-14. The optimized compound, NT-7-16, was evaluated in biological assays that confirm that it has potent activities as a new colchicine site microtubule depolymerizer. NT-7-16 exhibits antiproliferative and cytotoxic activities against multiple cancer cell lines, with IC(50) values of 10-16 nM, and it is able to overcome drug resistance mediated by the expression of P-glycoprotein and the ßIII isotype of tubulin. NT-7-16 initiated the concentration-dependent loss of cellular microtubules and caused the formation of abnormal mitotic spindles, leading to mitotic accumulation. The direct interaction of NT-7-16 with purified tubulin was confirmed, and it was more potent than combretastatin A-4 in these assays. Binding studies verified that NT-7-16 binds to tubulin within the colchicine site. The antitumor effects of NT-7-16 were evaluated in an MDA-MB-435 xenograft model and it had excellent activity at concentrations that were not toxic. A second compound, NT-9-21, which contains dichloro moieties in place of the 3,5-dibromo substituents of NT-7-16, had a poorer fit within the colchicine site as predicted by modeling and the Hydropathic INTeractions score. Biological evaluations showed that NT-9-21 has 10-fold lower potency than NT-7-16, confirming the modeling predictions. These studies highlight the value of the refined colchicine-site model and identify a new pyrrole-based colchicine-site agent with potent in vitro activities and promising in vivo antitumor actions.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Pirróis / Tubulina (Proteína) / Colchicina / Simulação de Acoplamento Molecular Tipo de estudo: Prognostic_studies Limite: Animals / Female / Humans Idioma: En Ano de publicação: 2016 Tipo de documento: Article
Texto completo
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XML
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Pirróis / Tubulina (Proteína) / Colchicina / Simulação de Acoplamento Molecular Tipo de estudo: Prognostic_studies Limite: Animals / Female / Humans Idioma: En Ano de publicação: 2016 Tipo de documento: Article