Disease relevance of methyl (2S)-2-[[4-[[(2R)-2-amino-3-sulfanyl-propyl]amino]-2-phenyl-phenyl]carbonylamino]-4-methylsulfanyl-butanoate

• FTI-277 revealed strong toxicity toward normal purified CD34+ cells [1].
• Using breast tumor models, we show that agents possessing a lactone moiety, including statins (such as lovastatin) and the isoprenoid inhibitors (such as FTI-277 and GGTI-298), mediate their cell cycle inhibitory activities by blocking the chymotrypsin activity of the proteasome in vitro [2].
• Herein, we demonstrate that in the human lung adenocarcinoma A549 cells, GGTI-298 induced a G1-G0 block whereas FTI-277 induced an enrichment in the G2-M phase of the cell cycle [3].
• FTI-277 accumulated Calu-1 and A-549 lung carcinoma and Colo 357 pancreatic carcinoma cells in G2/M, T-24 bladder carcinoma, and HT-1080 fibrosarcoma cells in G0/G1, but had no effect on cell cycle distribution of pancreatic (Panc-1), breast (SKBr 3 and MDAMB-231), and head and neck (A-253) carcinoma cells [4].
• By contrast, concentrations of FTI-277 (a specific inhibitor of farnesyl transferase) that prevented protein farnesylation in purified rabbit osteoclasts had little effect on osteoclast morphology or apoptosis and did not inhibit bone resorption [5].

High impact information on methyl (2S)-2-[[4-[[(2R)-2-amino-3-sulfanyl-propyl]amino]-2-phenyl-phenyl]carbonylamino]-4-methylsulfanyl-butanoate

• Such mice were then treated with the prenylation inhibitors FTI-277 and FTI-2153 [6].
• Targeting geranylgeranyl transferase (GGTase) and Rho kinase by specific inhibitors (GGTI-298 and Y-27632), but not inhibition of farnesyl transferase (FTase) by FTI-277, showed similar reduction of CAM-DR [7].
• Treatment of NB-4 cells with FTI-277 primarily resulted in a G2/M block, whereas treatment with FPT-3 and U0126 led to induction of apoptosis [1].
• In contrast to most inhibitors (eg, B581, Cys-4-Abs-Met, FPT-2, FTI-276, and FTS), a significant growth inhibition was only observed for FTI-277 (19 of 19), FPT-3 (10 of 19), and the MEK inhibitors U0126 (19 of 19) and PD098059 (8 of 19) [1].
• Inhibition of Ras processing obtained with FTI-277, an inhibitor of farnesyltransferase, resulted in detectable effects only at high doses [8].

Chemical compound and disease context of methyl (2S)-2-[[4-[[(2R)-2-amino-3-sulfanyl-propyl]amino]-2-phenyl-phenyl]carbonylamino]-4-methylsulfanyl-butanoate

• Since the mechanisms of action of these 2 classes of drugs are different, we tested the combination of tamoxifen and FTI-277 on inhibiting proliferation of hormone-dependent MCF-7 human breast cancer cells [9].

Biological context of methyl (2S)-2-[[4-[[(2R)-2-amino-3-sulfanyl-propyl]amino]-2-phenyl-phenyl]carbonylamino]-4-methylsulfanyl-butanoate

• While the processing of H-Ras was very sensitive to inhibition by FTI-277 (IC50 = 100 nM), that of K-Ras4B was highly resistant (IC50 = 10 microM) [10].
• Treatment of the human pancreatic tumor cell line, Panc-1, with FTI-277 enhanced the ability of TGFbeta to inhibit both anchorage-dependent and -independent tumor cell growth [11].
• Farnesyl transferase inhibitor FTI-277 prevents the membrane association of the CAAX motif and thus increases the cytoplasmic levels of the eIF4G fusion protein, which is then capable of inducing translation of the second cistron of a bicistronic messenger RNA containing an R17-binding site in its intercistronic space [12].
• Here we show that FTI-277, another farnesyltransferase inhibitor, prevented the production of complete, infectious HDV virions of two different genotypes [13].
• Ras inhibition with the specific inhibitor FTI-277 showed that downregulation of Fas in the ras transfectants could be reversed [14].

Anatomical context of methyl (2S)-2-[[4-[[(2R)-2-amino-3-sulfanyl-propyl]amino]-2-phenyl-phenyl]carbonylamino]-4-methylsulfanyl-butanoate

• The farnesyltransferase inhibitor FTI-277 radiosensitizes H-ras-transformed rat embryo fibroblasts [15].
• In the present study, we found that the dominant-negative version of Ras (RasN17) and specific Ras inhibitor, FTI-277, inhibited CpG ODN-induced nitric oxide (NO) and tumor necrosis factor-alpha (TNF-alpha) production by murine macrophage cell line RAW264 [16].
• Although NE10790 was a poor inhibitor of FPP synthase, it did inhibit prenylation in J774 macrophages and osteoclasts, but only of proteins of molecular mass approximately 22-26 kDa, the prenylation of which was not affected by peptidomimetic inhibitors of either farnesyl transferase (FTI-277) or geranylgeranyl transferase I (GGTI-298) [17].
• However, Ras inactivation by pharmacological disruption with the farnesyl transferase inhibitor, FTI-277, had no adverse effect on the ability of NK cells to lyse tumor cells or to express MAPK activation upon target conjugation [18].
• The protein farnesyltransferase inhibitor, FTI-277, had no effect on leukocyte adhesion induced by either stimulus [19].

Associations of methyl (2S)-2-[[4-[[(2R)-2-amino-3-sulfanyl-propyl]amino]-2-phenyl-phenyl]carbonylamino]-4-methylsulfanyl-butanoate with other chemical compounds

• While inhibition of processing and signaling of oncogenic K-Ras4B is more sensitive to the geranylgeranyltransferase I (GGTase I) inhibitor GGTI-286 than it is to FTI-277 in K-Ras4B-transformed NIH3T3 cells, the sensitivity of K-Ras as well as H- and N-Ras to the CAAX peptidomimetics in human tumor cell lines is not known [20].
• The geranylgeranyl transferase GGTI-298 inhibitor mimicked the effects of lovastatin on cell morphology and induced cell death, whereas the farnesyl transferase inhibitor FTI-277 was less effective to induce both cell rounding and apoptosis [21].
• Cells deprived of estradiol were analyzed for ERE-dependent luciferase activity 16 hours after estradiol stimulation and treatment with FTI-277 (a farnesyltransferase inhibitor) or with GGTI-298 (a geranylgeranyltransferase I inhibitor) [22].

Gene context of methyl (2S)-2-[[4-[[(2R)-2-amino-3-sulfanyl-propyl]amino]-2-phenyl-phenyl]carbonylamino]-4-methylsulfanyl-butanoate

• When cells are treated with FTI-277, a selective farnesyltransferase inhibitor, PRL-1, -2, and -3 shifted into the nucleus [23].
• Furthermore, treatment of Calu-1, Panc-1, Colo 357, T-24, A-253, SKBr 3, and MDAMB-231 cells with GGTI-298, but not FTI-277, induced the protein expression levels of the cyclin-dependent kinase inhibitor p21WAF [4].
• Third, treatment with the farnesyltransferase inhibitor FTI-277 blocked Ras, but not Src, transformation [24].
• In RK3E epithelial cells, the MEK1/2 inhibitors also eliminated transformation, but FTI-277 only partially inhibited transformation [25].
• FTI-277 did not suppress the proliferation of BRAF-mutant cells (WiDr and TCO), but remarkably inhibited the growth of K-ras mutant cells (LoVo) [26].

References