Selective cytotoxicity of a bicyclic Ras inhibitor in cancer cells expressing K-Ras(G13D).
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.
Palmioli
Alessandro
A
Department of Biotechnology and Biosciences, University of Milano-Bicocca, Piazza della Scienza, 20126 Milan, Italy.
Sacco
Elena
E
Airoldi
Cristina
C
Di Nicolantonio
Federica
F
D'Urzo
Annalisa
A
Shirasawa
Senji
S
Sasazuki
Takehiko
T
Di Domizio
Alessandro
A
De Gioia
Luca
L
Martegani
Enzo
E
Bardelli
Alberto
A
Peri
Francesco
F
Vanoni
Marco
M
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
D000970:Antineoplastic Agents; D001643:Bridged Bicyclo Compounds; D020666:ras-GRF1; D016283:Proto-Oncogene Proteins p21(ras)