Post-translational protein prenylation, a process catalyzed by three different enzymes, occurs at the C-terminal of a number of proteins involved in cell growth control and oncogenesis. One of these enzymes, geranylgeranyltransferase I (GGTase I) modifies cysteines of proteins with CAAX terminal sequences, preferring either leucine or isoleucine in the X-position. The Rho family of proteins are typically geranylgeranylated by GGTase I. GGTI 298 is a CAAX peptidomimetic that selectively inhibits GGTase I with little effect on other prenylation enzymes such as farnesyltransferase. It has been shown to arrest human tumor cells (IC50 = 10 μM for A549 cells) in G0/G1 and induce apoptosis by inhibiting proteasome activity and up-regulating the expression of the cyclin-dependent kinase inhibitor p21.
