title: Inhibition of K-ras-transformed rodent and human cancer cell growth via induction of apoptosis by irreversible inhibitors of Ras endoprotease.
abstract: Proteolytic removal of the carboxyl terminal tripeptide of Ras oncoproteins is important in the Ras function. Two chloromethyl ketones, BFCCMK and UM96001, designed to be the Ras C-terminal sequence-specific endoprotease inhibitors, at low micromolar concentrations (5.0 microM), potently inhibit the growth of ras-transformed rodent and human cancer cells, whereas untransformed NIH/3T3 cells are not affected under the same conditions. Furthermore, BFCCMK and UM96001 block more than 98% of the anchorage-independent clonogenic growth of ras-transformed rat and human cancer cells at low micromolar concentrations. The blocking of cancer cell growth may be due to the selective induction of apoptosis of ras-transformed cells by these inhibitors. These results provide the first experimental evidence that the endoproteolysis of Ras oncoproteins is important for the growth and apoptosis of ras-transformed cancer cells. Therefore, the Ras C-terminal sequence-specific endoprotease may be a potential new target for the treatment of human cancers induced by ras mutations.
authors.affiliation: Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota Academic Health Center, Minneapolis 55455, USA. chenx112@gold.tc.umn.edu
authors.forename: Y
authors.initials: Y
authors.lastname: Chen
mesh_terms: D016475:3T3 Cells; D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis; D002455:Cell Division / Q000187:drug effects; D002461:Cell Line, Transformed; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D011905:Genes, ras; D006801:Humans; D051379:Mice; D010169:Palmitic Acids / Q000494:pharmacology*; D051381:Rats; D018631:ras Proteins / Q000037:antagonists & inhibitors*
chemical_list: D000590:Amino Acid Chloromethyl Ketones; C116012:BFCCCMK; D004791:Enzyme Inhibitors; D010169:Palmitic Acids; C116011:UM 96001; D018631:ras Proteins