title: A-432411, a novel indolinone compound that disrupts spindle pole formation and inhibits human cancer cell growth.
abstract: Microtubules are among the most successful targets for anticancer therapies and for the development of new anticancer drugs. A-432411 is a novel small molecule that destabilizes microtubules at high concentration and disrupts normal spindle formation at low concentration. A-432411 is an indolinone that is structurally different from other known synthetic microtubule inhibitors. This compound is efficacious against a variety of human cancer cell lines including drug-resistant HCT-15 that overexpresses Pgp170. Biochemical studies show that A-432411 competes with the colchicine-binding site on tubulin and inhibits microtubule polymerization. Fluorescence-activated cell sorting analysis indicates that A-432411 causes G2-M arrest and induces apoptosis. Cells treated with A-432411 have increased level of phospho-histone H3 at Ser10 and decreased level of phospho-cdc2 at Tyr15. Concurrently, securin and cyclin B1 expression levels remain the same, indicating the activation of the spindle checkpoint. Immunocytochemistry and fluorescence microscopy experiments reveal that 1 micromol/L A-432411 destabilizes microtubules in cells. At 0.1 micromol/L, the compound disrupts normal spindle pole formation possibly through stabilization of microtubule dynamic. Both structural and cellular properties of A-432411 make it an attractive candidate for further development.
authors.affiliation: Cancer Research, Abbott Laboratories, Global Pharmaceutical Research and Development, Department 47B, AP10/114, 100 Abbott Park Road, Abbott Park, IL 60064, USA. zehan.chen@abbott.com
authors.forename: Zehan
authors.initials: Z
authors.lastname: Chen
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Merta
authors.forename: Nan-Hong
authors.initials: NH
authors.lastname: Lin
authors.forename: Stephen K
authors.initials: SK
authors.lastname: Tahir
authors.forename: Peter
authors.initials: P
authors.lastname: Kovar
authors.forename: Hing L
authors.initials: HL
authors.lastname: Sham
authors.forename: Haiying
authors.initials: H
authors.lastname: Zhang
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D001667:Binding, Competitive; D015153:Blotting, Western; D016203:CDC2 Protein Kinase / Q000378:metabolism; D002453:Cell Cycle; D016923:Cell Death; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002469:Cell Separation; D003078:Colchicine / Q000494:pharmacology; D019926:Cyclin B / Q000737:chemistry; D056744:Cyclin B1; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000378:metabolism; D005434:Flow Cytometry; D006367:HeLa Cells; D006657:Histones / Q000737:chemistry; D006801:Humans; D007150:Immunohistochemistry; D007211:Indoles / Q000737:chemistry* / Q000494:pharmacology; D008856:Microscopy, Fluorescence; D008870:Microtubules / Q000737:chemistry / Q000378:metabolism; D008956:Models, Chemical; D009363:Neoplasm Proteins / Q000737:chemistry; D011758:Pyrroles / Q000737:chemistry* / Q000494:pharmacology*; D064249:Securin; D008941:Spindle Apparatus / Q000187:drug effects*; D013997:Time Factors; D014404:Tubulin / Q000737:chemistry; D014443:Tyrosine / Q000737:chemistry
chemical_list: C504346:6-(4-hydroxy-3-methoxyphenyl)-3-(1H-pyrrol-2-ylmethylene)-1,3-dihydroindol-2-one; D000970:Antineoplastic Agents; C534699:CCNB1 protein, human; D019926:Cyclin B; D056744:Cyclin B1; D006657:Histones; D007211:Indoles; D009363:Neoplasm Proteins; D011758:Pyrroles; D064249:Securin; D014404:Tubulin; C578002:pituitary tumor-transforming protein 1, human; D014443:Tyrosine; D016203:CDC2 Protein Kinase; D003078:Colchicine