title: Selective cytotoxicity of a bicyclic Ras inhibitor in cancer cells expressing K-Ras(G13D).
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-Ras(G13D), 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.
authors.affiliation: Department of Biotechnology and Biosciences, University of Milano-Bicocca, Piazza della Scienza, 20126 Milan, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Palmioli
authors.forename: Elena
authors.initials: E
authors.lastname: Sacco
authors.forename: Cristina
authors.initials: C
authors.lastname: Airoldi
authors.forename: Federica
authors.initials: F
authors.lastname: Di Nicolantonio
authors.forename: Annalisa
authors.initials: A
authors.lastname: D'Urzo
authors.forename: Senji
authors.initials: S
authors.lastname: Shirasawa
authors.forename: Takehiko
authors.initials: T
authors.lastname: Sasazuki
authors.forename: Alessandro
authors.initials: A
authors.lastname: Di Domizio
authors.forename: Luca
authors.initials: L
authors.lastname: De Gioia
authors.forename: Enzo
authors.initials: E
authors.lastname: Martegani
authors.forename: Alberto
authors.initials: A
authors.lastname: Bardelli
authors.forename: Francesco
authors.initials: F
authors.lastname: Peri
authors.forename: Marco
authors.initials: M
authors.lastname: Vanoni
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001643:Bridged Bicyclo Compounds / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D009154:Mutation; D016283:Proto-Oncogene Proteins p21(ras) / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D020666:ras-GRF1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D001643:Bridged Bicyclo Compounds; D020666:ras-GRF1; D016283:Proto-Oncogene Proteins p21(ras)