| Autor: |
G P, Prevost, A, Pradines, I, Viossat, M C, Brezak, K, Miquel, M O, Lonchampt, P, Kasprzyk, G, Favre, B, Pignol, C, Le Breton, J, Dong, B, Morgan |
| Rok vydání: |
1999 |
| Předmět: |
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| Zdroj: |
International journal of cancer. 83(2) |
| ISSN: |
0020-7136 |
| Popis: |
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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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