GGTIs

GGTIs, or geranylgeranyltransferase inhibitors, are a class of small molecules that inhibit the enzyme geranylgeranyltransferase. The enzyme catalyzes the transfer of the 20-carbon isoprenoid geranylgeranyl group from geranylgeranyl pyrophosphate to cysteine residues in proteins bearing a CaaX motif, a post-translational modification required for membrane association and activity of many small GTPases such as Rho, Rac, and Cdc42. By preventing prenylation, GGTIs disrupt proper localization and signaling, leading to reduced cell proliferation, altered cytoskeletal dynamics, and sometimes cell death. GGTIs are studied primarily as research tools to dissect the role of protein prenylation in cellular processes and as potential anti-cancer compounds.

Most GGTIs target GGTase I, the enzyme responsible for geranylgeranylation of most CaaX-containing substrates. A smaller subset shows activity against GGTase II (Rab-geranylgeranyltransferase), which modifies Rab family proteins. Inhibitors may be substrate-competitive, mimicking the CaaX motif, or non-competitive, binding to other parts of the enzyme. Common experimental GGTIs include peptidomimetic compounds that resemble the C-terminus of GGTase I substrates, such as GGTI-298 and GGTI-2133, which have been used to probe prenylation-dependent processes. More recent chemistries explore nonpeptidic scaffolds to improve cell permeability and selectivity.

Clinical development of GGTIs has faced challenges, including compensatory pathways and toxicity, limiting progress beyond preclinical studies. Nevertheless, GGTIs remain a tool for understanding prenylation biology and a potential route for combination therapies in oncology, where dependence on prenylated GTPases may be exploited.

See also: protein prenylation; farnesyltransferase inhibitors.