title: Identification of a nonkinase target mediating cytotoxicity of novel kinase inhibitors.
abstract: In developing inhibitors of the LIM kinases, the initial lead molecules combined potent target inhibition with potent cytotoxic activity. However, as subsequent compounds were evaluated, the cytotoxic activity separated from inhibition of LIM kinases. A rapid determination of the cytotoxic mechanism and its molecular target was enabled by integrating data from two robust core technologies. High-content assays and gene expression profiling both indicated an effect on microtubule stability. Although the cytotoxic compounds are still kinase inhibitors, and their structures did not predict tubulin as an obvious target, these results provided the impetus to test their effects on microtubule polymerization directly. Unexpectedly, we confirmed tubulin itself as a molecular target of the cytotoxic kinase inhibitor compounds. This general approach to mechanism of action questions could be extended to larger data sets of quantified phenotypic and gene expression data.
authors.affiliation: Bristol-Myers Squibb Research and Development, Princeton, NJ 08543-5400, USA.
authors.forename: Petra
authors.initials: P
authors.lastname: Ross-Macdonald
authors.forename: Heshani
authors.initials: H
authors.lastname: de Silva
authors.forename: Qi
authors.initials: Q
authors.lastname: Guo
authors.forename: Hong
authors.initials: H
authors.lastname: Xiao
authors.forename: Chen-Yi
authors.initials: CY
authors.lastname: Hung
authors.forename: Becky
authors.initials: B
authors.lastname: Penhallow
authors.forename: Jay
authors.initials: J
authors.lastname: Markwalder
authors.forename: Liqi
authors.initials: L
authors.lastname: He
authors.forename: Ricardo M
authors.initials: RM
authors.lastname: Attar
authors.forename: Tai-an
authors.initials: TA
authors.lastname: Lin
authors.forename: Steven
authors.initials: S
authors.lastname: Seitz
authors.forename: Charles
authors.initials: C
authors.lastname: Tilford
authors.forename: Judith
authors.initials: J
authors.lastname: Wardwell-Swanson
authors.forename: Donald
authors.initials: D
authors.lastname: Jackson
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000633:toxicity*; D004354:Drug Screening Assays, Antitumor; D020869:Gene Expression Profiling; D006801:Humans; D054461:Lim Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008856:Microscopy, Fluorescence; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000633:toxicity*; D014404:Tubulin / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D014404:Tubulin; D054461:Lim Kinases