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

Research output: Contribution to journalArticle

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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

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Cytotoxicity
ras Proteins
Nucleotides
Cells
ras Guanine Nucleotide Exchange Factors
Neoplasms
Arabinose
Mutant Proteins
Tumors
Colorectal Neoplasms
Genes
Nuclear magnetic resonance
Mutation
Experiments

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Biophysics
  • Cell Biology
  • Molecular Biology

Cite this

Palmioli, A., Sacco, E., Airoldi, C., Di Nicolantonio, F., D'Urzo, A., Shirasawa, S., ... 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

Selective cytotoxicity of a bicyclic Ras inhibitor in cancer cells expressing K-RasG13D . / Palmioli, Alessandro; Sacco, Elena; Airoldi, Cristina; Di Nicolantonio, Federica; D'Urzo, Annalisa; Shirasawa, Senji; Sasazuki, Takehiko; Di Domizio, Alessandro; De Gioia, Luca; Martegani, Enzo; Bardelli, Alberto; Peri, Francesco; Vanoni, Marco.

In: Biochemical and Biophysical Research Communications, Vol. 386, No. 4, 04.09.2009, p. 593-597.

Research output: Contribution to journalArticle

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, vol. 386, no. 4, pp. 593-597. https://doi.org/10.1016/j.bbrc.2009.06.069
Palmioli, Alessandro ; Sacco, Elena ; Airoldi, Cristina ; Di Nicolantonio, Federica ; D'Urzo, Annalisa ; Shirasawa, Senji ; Sasazuki, Takehiko ; Di Domizio, Alessandro ; De Gioia, Luca ; Martegani, Enzo ; Bardelli, Alberto ; Peri, Francesco ; Vanoni, Marco. / Selective cytotoxicity of a bicyclic Ras inhibitor in cancer cells expressing K-RasG13D . In: Biochemical and Biophysical Research Communications. 2009 ; Vol. 386, No. 4. pp. 593-597.
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