Protein farnesyltransferase (FTase) (FTase)

Protein farnesyltransferase (FTase) is a heterodimeric enzyme responsible for the post-translational attachment of a 15-carbon farnesyl isoprenoid group to the cysteine residue of the C-terminal CAAX motif of various proteins, most notably the RAS GTPase family [UniProt]. This modification, known as prenylation, is essential for the membrane anchoring and biological activity of RAS proteins, which act as molecular switches in signaling pathways governing cell growth and survival [PubMed: PMC2746353]. In many cancers, RAS is constitutively active due to mutations, making the blockade of its membrane localization an attractive therapeutic strategy [Nature Reviews Cancer]. While farnesyltransferase inhibitors (FTIs) like lonafarnib and tipifarnib effectively block HRAS function, their efficacy in KRAS-driven cancers is limited by escape mechanisms where KRAS undergoes alternative prenylation by geranylgeranyltransferase I (GGTase-I) [PubMed: 11753484]. Beyond oncology, FTase inhibition has proven clinically significant in treating Hutchinson-Gilford Progeria Syndrome by preventing the prenylation of the toxic protein progerin [FDA]. The therapeutic challenge remains the high degree of redundancy in the prenylation pathway, which often necessitates combination therapies or dual inhibitors [Journal of Biological Chemistry].

Other names

Farnesyl-protein transferaseCAAX farnesyltransferaseFPTaseProtein prenyltransferase

Inhibition of the farnesyltransferase enzyme to prevent the post-translational attachment of a farnesyl group to the CAAX motif of RAS proteins, thereby blocking their membrane association and downstream signaling.