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

Palmioli, A., Sacco, E., Airoldi, C., Di Nicolantonio, F., D'Urzo, A., Shirasawa, S., et al. (2009). Selective cytotoxicity of a bicyclic Ras inhibitor in cancer cells expressing K-RasG13D. BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 386(4), 593-597 [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;D'URZO, ANNALISA;DI DOMIZIO, ALESSANDRO;DE GIOIA, LUCA;MARTEGANI, ENZO;PERI, FRANCESCO;VANONI, MARCO ERCOLE
2009

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
Articolo in rivista - Articolo scientifico
HCT-116 cells, NMR, Nucleotide dissociation/exchange, Ras mutant, Ras inhibitor,
English
Palmioli, A., Sacco, E., Airoldi, C., Di Nicolantonio, F., D'Urzo, A., Shirasawa, S., et al. (2009). Selective cytotoxicity of a bicyclic Ras inhibitor in cancer cells expressing K-RasG13D. BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 386(4), 593-597 [10.1016/j.bbrc.2009.06.069].
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
File in questo prodotto:
File Dimensione Formato  
mmc1.doc

accesso aperto

Dimensione 18.75 MB
Formato Microsoft Word
18.75 MB Microsoft Word Visualizza/Apri

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/10281/7490
Citazioni
  • Scopus 32
  • ???jsp.display-item.citation.isi??? 29
Social impact