| Autor: |
Prevost, Grégoire P., Pradines, Anne, Viossat, Isabelle, Brezak, Marie-Christine, Miquel, Karine, Lonchampt, Marie-Odile, Kasprzyk, Philip, Favre, Gilles, Pignol, Bernadette, Breton, Christine Le, Dong, Jesse, Morgan, Barry |
| Zdroj: |
International Journal of Cancer; 8 October 1999, Vol. 83 Issue: 2 p283-287, 5p |
| Abstrakt: |
Oncogenic mutations of the ras gene leading to constitutive activation of downstream effectors have been detected in a large spectrum of human cancers (pancreas, thyroid, colon and NSCLC). Membrane anchorage of Ras required for functional activity in signal transduction is facilitated by post-translational modifications resulting in covalent attachment of a farnesyl group to the cysteine in the C-terminal CAAX motif. This attachment is mediated by farnesyltransferase (FTase). Here, we report a novel series of potent FTase inhibitors, where the tetrapeptide CAAX motif has been modified by incorporation of a thiazolidine carboxylic acid moiety followed by reduction of the 1st and 2nd peptide bonds to a secondary and tertiary amine, respectively. The C-terminal carboxylate was converted to esters for improved cellular penetration. These compounds showed specific inhibition of purified human FTase enzyme, inhibition of proliferation in vitro in a large spectrum of human tumor cell lines and inhibition of growth of human tumor xenografts in athymic nude mice. In addition, in regard to a panel of cell lines, using the Compare analysis to determine the Pearson coefficient correlation, the anti-proliferative spectrum of BIM-46068 has been shown to be distinct from the profile of typical chemotherapeutic agents. Int. J. Cancer 83:283287, 1999. © 1999 Wiley-Liss, Inc. |
| Databáze: |
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