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Chemical Compound Review

AC1MHIZU     [(2R)-1-[[4-[[(1S)-1- methoxycarbonyl-3...

Synonyms: ZINC03821325
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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

  1. Cell-cycle-dependent activation of mitogen-activated protein kinase kinase (MEK-1/2) in myeloid leukemia cell lines and induction of growth inhibition and apoptosis by inhibitors of RAS signaling. Morgan, M.A., Dolp, O., Reuter, C.W. Blood (2001) [Pubmed]
  2. Farnesyl and geranylgeranyl transferase inhibitors induce G1 arrest by targeting the proteasome. Efuet, E.T., Keyomarsi, K. Cancer Res. (2006) [Pubmed]
  3. GGTI-298 induces G0-G1 block and apoptosis whereas FTI-277 causes G2-M enrichment in A549 cells. Miquel, K., Pradines, A., Sun, J., Qian, Y., Hamilton, A.D., Sebti, S.M., Favre, G. Cancer Res. (1997) [Pubmed]
  4. The geranylgeranyltransferase-I inhibitor GGTI-298 arrests human tumor cells in G0/G1 and induces p21(WAF1/CIP1/SDI1) in a p53-independent manner. Vogt, A., Sun, J., Qian, Y., Hamilton, A.D., Sebti, S.M. J. Biol. Chem. (1997) [Pubmed]
  5. Protein geranylgeranylation is required for osteoclast formation, function, and survival: inhibition by bisphosphonates and GGTI-298. Coxon, F.P., Helfrich, M.H., Van't Hof, R., Sebti, S., Ralston, S.H., Hamilton, A., Rogers, M.J. J. Bone Miner. Res. (2000) [Pubmed]
  6. In vivo antiviral efficacy of prenylation inhibitors against hepatitis delta virus. Bordier, B.B., Ohkanda, J., Liu, P., Lee, S.Y., Salazar, F.H., Marion, P.L., Ohashi, K., Meuse, L., Kay, M.A., Casey, J.L., Sebti, S.M., Hamilton, A.D., Glenn, J.S. J. Clin. Invest. (2003) [Pubmed]
  7. The HMG-CoA reductase inhibitor simvastatin overcomes cell adhesion-mediated drug resistance in multiple myeloma by geranylgeranylation of Rho protein and activation of Rho kinase. Schmidmaier, R., Baumann, P., Simsek, M., Dayyani, F., Emmerich, B., Meinhardt, G. Blood (2004) [Pubmed]
  8. Tyrosine phosphorylation of focal adhesion kinase by PDGF is dependent on ras in human hepatic stellate cells. Carloni, V., Pinzani, M., Giusti, S., Romanelli, R.G., Parola, M., Bellomo, G., Failli, P., Hamilton, A.D., Sebti, S.M., Laffi, G., Gentilini, P. Hepatology (2000) [Pubmed]
  9. Additive effects of tamoxifen and the farnesyl transferase inhibitor FTI-277 on inhibition of MCF-7 breast cancer cell-cycle progression. Doisneau-Sixou, S.F., Cestac, P., Faye, J.C., Favre, G., Sutherland, R.L. Int. J. Cancer (2003) [Pubmed]
  10. Disruption of oncogenic K-Ras4B processing and signaling by a potent geranylgeranyltransferase I inhibitor. Lerner, E.C., Qian, Y., Hamilton, A.D., Sebti, S.M. J. Biol. Chem. (1995) [Pubmed]
  11. Inhibition of farnesyltransferase increases TGFbeta type II receptor expression and enhances the responsiveness of human cancer cells to TGFbeta. Adnane, J., Bizouarn, F.A., Chen, Z., Ohkanda, J., Hamilton, A.D., Munoz-Antonia, T., Sebti, S.M. Oncogene (2000) [Pubmed]
  12. Pharmacological-based translational induction of transgene expression in mammalian cells. Boutonnet, C., Boijoux, O., Bernat, S., Kharrat, A., Favre, G., Faye, J.C., Vagner, S. EMBO Rep. (2004) [Pubmed]
  13. A prenylation inhibitor prevents production of infectious hepatitis delta virus particles. Bordier, B.B., Marion, P.L., Ohashi, K., Kay, M.A., Greenberg, H.B., Casey, J.L., Glenn, J.S. J. Virol. (2002) [Pubmed]
  14. Regulation of Fas-mediated apoptosis by N-ras in melanoma. Urquhart, J.L., Meech, S.J., Marr, D.G., Shellman, Y.G., Duke, R.C., Norris, D.A. J. Invest. Dermatol. (2002) [Pubmed]
  15. The farnesyltransferase inhibitor FTI-277 radiosensitizes H-ras-transformed rat embryo fibroblasts. Bernhard, E.J., Kao, G., Cox, A.D., Sebti, S.M., Hamilton, A.D., Muschel, R.J., McKenna, W.G. Cancer Res. (1996) [Pubmed]
  16. Ras participates in CpG oligodeoxynucleotide signaling through association with toll-like receptor 9 and promotion of interleukin-1 receptor-associated kinase/tumor necrosis factor receptor-associated factor 6 complex formation in macrophages. Xu, H., An, H., Yu, Y., Zhang, M., Qi, R., Cao, X. J. Biol. Chem. (2003) [Pubmed]
  17. Identification of a novel phosphonocarboxylate inhibitor of Rab geranylgeranyl transferase that specifically prevents Rab prenylation in osteoclasts and macrophages. Coxon, F.P., Helfrich, M.H., Larijani, B., Muzylak, M., Dunford, J.E., Marshall, D., McKinnon, A.D., Nesbitt, S.A., Horton, M.A., Seabra, M.C., Ebetino, F.H., Rogers, M.J. J. Biol. Chem. (2001) [Pubmed]
  18. Direct tumor lysis by NK cells uses a Ras-independent mitogen-activated protein kinase signal pathway. Wei, S., Gilvary, D.L., Corliss, B.C., Sebti, S., Sun, J., Straus, D.B., Leibson, P.J., Trapani, J.A., Hamilton, A.D., Weber, M.J., Djeu, J.Y. J. Immunol. (2000) [Pubmed]
  19. Integrin-dependent leukocyte adhesion involves geranylgeranylated protein(s). Liu, L., Moesner, P., Kovach, N.L., Bailey, R., Hamilton, A.D., Sebti, S.M., Harlan, J.M. J. Biol. Chem. (1999) [Pubmed]
  20. Inhibition of the prenylation of K-Ras, but not H- or N-Ras, is highly resistant to CAAX peptidomimetics and requires both a farnesyltransferase and a geranylgeranyltransferase I inhibitor in human tumor cell lines. Lerner, E.C., Zhang, T.T., Knowles, D.B., Qian, Y., Hamilton, A.D., Sebti, S.M. Oncogene (1997) [Pubmed]
  21. Prenyltransferase inhibitors induce apoptosis in proliferating thyroid cells through a p53-independent CrmA-sensitive, and caspase-3-like protease-dependent mechanism. Vitale, M., Di Matola, T., Rossi, G., Laezza, C., Fenzi, G., Bifulco, M. Endocrinology (1999) [Pubmed]
  22. Prenylation inhibitors stimulate both estrogen receptor alpha transcriptional activity through AF-1 and AF-2 and estrogen receptor beta transcriptional activity. Cestac, P., Sarrabayrouse, G., Médale-Giamarchi, C., Rochaix, P., Balaguer, P., Favre, G., Faye, J.C., Doisneau-Sixou, S. Breast Cancer Res. (2005) [Pubmed]
  23. Prenylation-dependent association of protein-tyrosine phosphatases PRL-1, -2, and -3 with the plasma membrane and the early endosome. Zeng, Q., Si, X., Horstmann, H., Xu, Y., Hong, W., Pallen, C.J. J. Biol. Chem. (2000) [Pubmed]
  24. Ras, but not Src, transformation of RIE-1 epithelial cells is dependent on activation of the mitogen-activated protein kinase cascade. Oldham, S.M., Cox, A.D., Reynolds, E.R., Sizemore, N.S., Coffey, R.J., Der, C.J. Oncogene (1998) [Pubmed]
  25. Roles of the Ras-MEK-mitogen-activated protein kinase and phosphatidylinositol 3-kinase-Akt-mTOR pathways in Jaagsiekte sheep retrovirus-induced transformation of rodent fibroblast and epithelial cell lines. Maeda, N., Fu, W., Ortin, A., de las Heras, M., Fan, H. J. Virol. (2005) [Pubmed]
  26. BRAF mutation associated with dysregulation of apoptosis in human colorectal neoplasms. Ikehara, N., Semba, S., Sakashita, M., Aoyama, N., Kasuga, M., Yokozaki, H. Int. J. Cancer (2005) [Pubmed]
 
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