Biological Activity
fti-277 is a highly potent and selective ftase inhibitor. at concentration as low as 10 nm, fti-277 inhibits h-ras processing and the processing is blocked by more than 95% at 3 μm. [1]ras proteins are plasma membrane-associated gtpases. it acts as relay switches transducing biological information from extracellular signals to the nucleus. farnesyltransferase (ftase) is an enzyme that catalyzed the ras farnesylation, a lipid posttranslational modification that is required for ras-induced malignant transformation. [1]fti-277, the methyl ester derivative of fti-276, is extremely potent (icgraphic = 100 nm) at inhibiting h-ras, but not the geranylgeranylated rap1a processing in whole cells. fti-277 is a farnesylation-specific inhibitor which inhibits the processing of both oncogenic and normal ras. [1]in mice that hydrodynamically transfected to produce hepatitis delta virus (hdv) viremia, fti-277 treatment is effective in inhibiting viremia. [2]
in vitro
FTI-277 inhibits Ras processing with an IC50 of 100 nM, but not the geranylgeranylated Rap1A processing in whole cells. It induces accumulation of cytoplasmic non-farnesylated H-Ras, accumulates inactive Ras/Raf complexes in the cytoplasm, and constitutive blocksive MAPK activation in H-RasF cells. It causes increased after irradiation and increases radiosensitivity in H-ras-transformed rat embryo cells. FTI-277 also inhibits cell growth and induces apoptosis in drug-resistant myeloma tumor cells. In SH- apoptosis SY5Y cells, It diminishes the toxic effects of methamphetamine on induction in cell degeneration, activation in c-Jun-N-terminal kinase cascades, and Ras activation.
in vivo
In mice coinfected with hepatitis B virus (HBV) and HDV, FTI-277 (50 mg/kg/d ip) effectively clears HDV viremia.
References
1. bordier bb, ohkanda j, liu p et al. in vivo antiviral efficacy of prenylation inhibitors against hepatitis delta virus. j clin invest. 2003 aug;112(3):407-14.2. lerner ec, qian y, blaskovich ma et al. ras caax peptidomimetic fti-277 selectively blocksoncogenic ras signaling by inducing cytoplasmic accumulation of inactive ras-raf complexes. j biol chem. 1995 nov 10;270(45):26802-6. pubmed pmid: 7592920.
