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Chemical Compound Review

AC1MHVGL     [(2R)-1-[[4-[[(1S)-1- methoxycarbonyl-3...

Synonyms: ZINC13796722
This record was replaced with 3012117.
 
 
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Disease relevance of methyl (2S)-2-[[4-[[(2R)-2-amino-3-sulfanyl-propyl]amino]-2-phenyl-benzoyl]amino]-4-methyl-pentanoate

  • FTI-277, GGTI-286, and GGTI-298 each produced a striking concentration-dependent antiproliferative effect on the glioma cell lines, with the median effective dose ranging from 2.5 to 15.5 micromol/L [1].
  • CONCLUSION: Our studies demonstrated that FTI-277, GGTI-286, and GGTI-298 each yielded significant antiproliferative effects in human malignant glioma cells in vitro at low micromolar concentrations, which have been achievable in vivo without major systemic toxicity [1].
  • Specific inhibition of geranylgeranyltransferase-I and Rac/Cdc42 by GGTI-286 and Clostridium sordellii lethal toxin, respectively, enhanced TM expression, whereas inactivation of Rho by Clostridium botulinum C3 exoenzyme was ineffective [2].
 

High impact information on methyl (2S)-2-[[4-[[(2R)-2-amino-3-sulfanyl-propyl]amino]-2-phenyl-benzoyl]amino]-4-methyl-pentanoate

  • Thrombin also rapidly stimulated GTP loading of RhoA, which was blocked by acute pretreatment with either atorvastatin or GGTI-286 [3].
  • Thrombin-induced rapid geranylgeranylation was inhibited by acute short term (3 min) pretreatment with atorvastatin as well as by an inhibitor of GGTase I (GGTI-286) [3].
  • Furthermore, GGTI-286 is highly selective for geranylgeranylation over farnesylation since it inhibited the processing of farnesylated H-Ras only at much higher concentrations (IC50 > 30 microM) [4].
  • A similar effect is observed by GGTI-286, a geranylgeranyl transferase inhibitor, suggesting that the association of Rho with the cortical granules is indispensable for its function [5].
  • An inhibitor of geranylgeranyltransferase, GGTI-286, mimics the effects of statins, indicating geranylgeranylation is key to MPO expression [6].
 

Biological context of methyl (2S)-2-[[4-[[(2R)-2-amino-3-sulfanyl-propyl]amino]-2-phenyl-benzoyl]amino]-4-methyl-pentanoate

  • In contrast, we found the processing of K-Ras4B to be much more sensitive to GGTI-286 (IC50 = 2 microM) [4].
 

Anatomical context of methyl (2S)-2-[[4-[[(2R)-2-amino-3-sulfanyl-propyl]amino]-2-phenyl-benzoyl]amino]-4-methyl-pentanoate

 

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

 

Gene context of methyl (2S)-2-[[4-[[(2R)-2-amino-3-sulfanyl-propyl]amino]-2-phenyl-benzoyl]amino]-4-methyl-pentanoate

  • Furthermore, GGTI-286, but not FTI-277, mimicked the effect of simvastatin by increasing the TNF-alpha-mediated overexpression of E-selectin [9].
  • The same experiments were performed with selective inhibitors of geranylgeranyltransferase (GGTI-286) and farnesyltransferase (FTI-277) [9].

References

  1. Inhibition of Ras and related G-proteins as a therapeutic strategy for blocking malignant glioma growth. Bredel, M., Pollack, I.F., Freund, J.M., Hamilton, A.D., Sebti, S.M. Neurosurgery (1998) [Pubmed]
  2. Pitavastatin-induced thrombomodulin expression by endothelial cells acts via inhibition of small G proteins of the Rho family. Masamura, K., Oida, K., Kanehara, H., Suzuki, J., Horie, S., Ishii, H., Miyamori, I. Arterioscler. Thromb. Vasc. Biol. (2003) [Pubmed]
  3. Thrombin-induced rapid geranylgeranylation of RhoA as an essential process for RhoA activation in endothelial cells. Ohkawara, H., Ishibashi, T., Sakamoto, T., Sugimoto, K., Nagata, K., Yokoyama, K., Sakamoto, N., Kamioka, M., Matsuoka, I., Fukuhara, S., Sugimoto, N., Takuwa, Y., Maruyama, Y. J. Biol. Chem. (2005) [Pubmed]
  4. 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]
  5. A Rho-signaling pathway mediates cortical granule translocation in the sea urchin oocyte. Covián-Nares, F., Martínez-Cadena, G., López-Godínez, J., Voronina, E., Wessel, G.M., García-Soto, J. Mech. Dev. (2004) [Pubmed]
  6. Statins downregulate myeloperoxidase gene expression in macrophages. Kumar, A.P., Reynolds, W.F. Biochem. Biophys. Res. Commun. (2005) [Pubmed]
  7. 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]
  8. Pharmacological modulation of fatty acid desaturation and of cholesterol biosynthesis in THP-1 cells. Risé, P., Ghezzi, S., Levati, M.G., Mirtini, R., Colombo, C., Galli, C. Lipids (2003) [Pubmed]
  9. Effects of statins on adhesion molecule expression in endothelial cells. Dimitrova, Y., Dunoyer-Geindre, S., Reber, G., Mach, F., Kruithof, E.K., de Moerloose, P. J. Thromb. Haemost. (2003) [Pubmed]
 
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