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Selective cytotoxicity of a bicyclic Ras inhibitor in cancer cells expressing K-Ras(G13D).
- Source :
-
Biochemical and biophysical research communications [Biochem Biophys Res Commun] 2009 Sep 04; Vol. 386 (4), pp. 593-7. Date of Electronic Publication: 2009 Jun 18. - Publication Year :
- 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-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.
- Subjects :
- Antineoplastic Agents chemistry
Bridged Bicyclo Compounds chemistry
Cell Line, Tumor
Humans
Magnetic Resonance Spectroscopy
Molecular Structure
Mutation
Proto-Oncogene Proteins p21(ras) biosynthesis
Proto-Oncogene Proteins p21(ras) genetics
ras-GRF1 genetics
ras-GRF1 metabolism
Antineoplastic Agents pharmacology
Bridged Bicyclo Compounds pharmacology
Proto-Oncogene Proteins p21(ras) antagonists & inhibitors
ras-GRF1 antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1090-2104
- Volume :
- 386
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Biochemical and biophysical research communications
- Publication Type :
- Academic Journal
- Accession number :
- 19540195
- Full Text :
- https://doi.org/10.1016/j.bbrc.2009.06.069