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¹ Cancer Research and ² Metabolic Disease, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois

Requests for reprints: Zehan Chen, Abbott Laboratories, Global Pharmaceutical Research and Development, Department 47B, AP10/114, 100 Abbott Park Road, Abbott Park, IL 60064. Phone: 847-935-5182; Fax: 847-935-7551. E-mail: zehan.chen{at}abbott.com

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 µmol/L A-432411 destabilizes microtubules in cells. At 0.1 µmol/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.

Key Words: A-432411 • antimitotics • microtubules • spindle poles

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³ Lin N-H, Ping X, Kovar P, et al. Synthesis and biological evaluation of 3-Ethylidine-1,3-dihydro-indol-2-one as novel checkpoint kinase 1 inhibitors. Abstracts of Papers, 229th ACS National Meeting, San Diego, CA, March, 2005, MEDI-146.

Received 9/ 1/04; revised 1/21/05; accepted 2/ 7/05.