Selective cytotoxicity of a bicyclic Ras inhibitor in cancer cells expressing K-RasG13D

Alessandro Palmioli, Elena Sacco, Cristina Airoldi, Federica Di Nicolantonio, Annalisa D'Urzo, Senji Shirasawa, Takehiko Sasazuki, Alessandro Di Domizio, Luca De Gioia, Enzo Martegani, Alberto Bardelli, Francesco Peri, Marco Vanoni

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Abstract

Mutation of RAS genes is a critical event in the pathogenesis of different human tumors and in some developmental disorders. Here we present an arabinose-derived bicyclic compound displaying selective cytotoxicity in human colorectal cancer cells expressing K-RasG13D, that shows high intrinsic nucleotide exchange rate. We characterize binding of bicyclic compounds by docking and NMR experiments and their inhibitory activity on GEF-mediated nucleotide exchange on wild-type and mutant Ras proteins. We demonstrate that the in vitro inhibition of Ras nucleotide exchange depends on the molar ratio between Ras and its GEF activator, suggesting that the observed in vivo selective effect may depend on biochemical parameters and actual intracellular concentration of the Ras protein and its regulators.

Original languageEnglish
Pages (from-to)593-597
Number of pages5
JournalBiochemical and Biophysical Research Communications
Volume386
Issue number4
DOIs
Publication statusPublished - Sep 4 2009
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

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  • Cite this

    Palmioli, A., Sacco, E., Airoldi, C., Di Nicolantonio, F., D'Urzo, A., Shirasawa, S., Sasazuki, T., Di Domizio, A., De Gioia, L., Martegani, E., Bardelli, A., Peri, F., & Vanoni, M. (2009). Selective cytotoxicity of a bicyclic Ras inhibitor in cancer cells expressing K-RasG13D. Biochemical and Biophysical Research Communications, 386(4), 593-597. https://doi.org/10.1016/j.bbrc.2009.06.069