Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

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Lanzi, C. et al.

Lanzi, Cassinelli, Pensa, Cassinis, Gambetta, Borrello, Menta, Pierotti, Zunino,

Inhibition of transforming activity of the ret/ptc1 oncoprotein by a 2-indolinone derivative.

ret-derived oncogenes are frequently and specifically expressed in thyroid tumors. In contrast to the ret receptor, ret oncoproteins are characterized by ligand-independent tyrosine-kinase activity and tyrosine phosphorylation. In this study, novel synthetic arylidene 2-indolinone compounds were evaluated as inhibitors of the ret/ptc1 tyrosine kinase. Four compounds inhibited ret/ptc1 activity in immunokinase assay (IC50 27-42 microM) including one (1,3-dihydro-5,6-dimethoxy-3-[(4-hydroxyphenyl) methylene)-2H-indol-2-one) (Cpd 1) that selectively inhibited the anchorage-independent growth of NIH3T3 transformants expressing the ret/ptc1 gene (NIH3T3ptc1 cells). Following exposure to Cpd 1, the transformed phenotype of NIH3T3ptc1 cells was reverted, within 24 hr, to a normal fibroblast-like morphology in adherent-cell culture. In these cells, the constitutive tyrosine phosphorylation of ret/ptc1, of the transducing adaptor protein shc and of a series of co-immunoprecipitated peptides became much reduced, as demonstrated by immunoprecipitation/Western-blot analyses. Data presented provide additional evidence that ret/ptc1 is directly implicated in malignant transformation, and demonstrate the ability of Cpd 1 to interfere in the signal transduction pathway constitutively activated by the ret/ptc1 oncoprotein. These results confirm the interest of the arylidene 2-indolinone class of tyrosine-kinase inhibitors as tools for the study of ret signaling and the control of cell proliferation in ret- and ret/ptcs-associated diseases.[1]

References

Inhibition of transforming activity of the ret/ptc1 oncoprotein by a 2-indolinone derivative. Lanzi, C., Cassinelli, G., Pensa, T., Cassinis, M., Gambetta, R.A., Borrello, M.G., Menta, E., Pierotti, M.A., Zunino, F. Int. J. Cancer (2000) [Pubmed]

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