Identification of a nonkinase target mediating cytotoxicity of novel kinase inhibitors.
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.
Ross-Macdonald
Petra
P
Bristol-Myers Squibb Research and Development, Princeton, NJ 08543-5400, USA.
de Silva
Heshani
H
Guo
Qi
Q
Xiao
Hong
H
Hung
Chen-Yi
CY
Penhallow
Becky
B
Markwalder
Jay
J
He
Liqi
L
Attar
Ricardo M
RM
Lin
Tai-an
TA
Seitz
Steven
S
Tilford
Charles
C
Wardwell-Swanson
Judith
J
Jackson
Donald
D
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
D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D014404:Tubulin; D054461:Lim Kinases