Selective inhibition of ras-transformed cell growth by a novel fatty acid-based chloromethyl ketone designed to target Ras endoprotease.

A novel fatty acid-based chloromethyl ketone, UM96001, which was designed to be a Ras C-terminal sequence-specific endoprotease inhibitor, at low micromolar concentrations (1-5.0 microM), potently inhibits ras-transformed rat kidney cell growth, whereas the growth of untransformed normal rat kidney cells is not affected under the same conditions. UM96001 almost completely blocks the anchorage-independent clonogenic growth of ras-transformed rat and human cancer cells at low micromolar concentrations. Inhibition of ras-transformed rat and human cancer cell growth by UM96001 may occur via the mechanism of selective induction of apoptosis of the cells. Furthermore, TPCK and BFCCMK, the known selective inhibitors of Ras C-terminal sequence-specific endoprotease, also yield similar inhibition results. These results provide the first experimental evidence that the endoproteolysis of Ras oncoproteins may be important for Ras-mediated cell growth and apoptosis. Therefore, the Ras C-terminal sequence-specific endoprotease may be a potential anticancer target.