A-432411, a novel indolinone compound that disrupts spindle pole formation and inhibits human cancer cell growth.
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.
Chen
Zehan
Z
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
Merta
Philip J
PJ
Lin
Nan-Hong
NH
Tahir
Stephen K
SK
Kovar
Peter
P
Sham
Hing L
HL
Zhang
Haiying
H
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
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