FGTI-2734 (FGTI2734) is a potent, CAAX tetrapeptide RAS C-terminal mimetic as dual farnesyltransferase (FT) and geranylgeranyltransferase-1 (GGT-1) inhibitor with IC50 of 250 and 520 nM, respectively.
FGTI-2734 inhibits both protein prenylation and membrane localization of KRAS and NRAS in RAS-transformed murine NIH3T3 cells and in mutant KRAS human cancer cells, but not the highly selective FTI-2148 or GGTI-2418.
FGTI-2734 inhibits the prenylation of both HDJ2 and RAP1A.
FGTI-2734 inhibits RAF-1 kinase activity although cytosolic KRAS binds RAF-1, it requires KSR and the membrane environment to fully activate RAF-1.
FGTI-2734 induces apoptosis in mutant KRAS-dependent, but not mutant KRAS-independent human cancer cells.
FGTI-2734 inhibits the in vivo growth of mutant KRAS-dependent but not mutant KRAS–independent human tumors in mouse xenograft models (100 mg/kg, i.p.), also inhibits the growth of mutant KRAS PDXs from patients with pancreatic cancer.