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.