Abstract:
: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.
journal_name
Int J Cancerjournal_title
International journal of cancerauthors
Prevost GP,Pradines A,Viossat I,Brezak MC,Miquel K,Lonchampt MO,Kasprzyk P,Favre G,Pignol B,Le Breton C,Dong J,Morgan Bdoi
10.1002/(sici)1097-0215(19991008)83:2<283::aid-ijckeywords:
subject
Has Abstractpub_date
1999-10-08 00:00:00pages
283-7issue
2eissn
0020-7136issn
1097-0215pii
10.1002/(SICI)1097-0215(19991008)83:2<283::AID-IJCjournal_volume
83pub_type
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