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Inhibition of human tumor cell growth In vitro and In vivo by a specific inhibitor of human farnesyltransferase: BIM‐46068
Author(s) -
Prevost Grégoire P.,
Pradines Anne,
Viossat Isabelle,
Brezak MarieChristine,
Miquel Karine,
Lonchampt MarieOdile,
Kasprzyk Philip,
Favre Gilles,
Pignol Bernadette,
Le Breton Christine,
Dong Jesse,
Morgan Barry
Publication year - 1999
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/(sici)1097-0215(19991008)83:2<283::aid-ijc22>3.0.co;2-6
Subject(s) - farnesyltransferase , farnesyltransferase inhibitor , in vivo , tetrapeptide , in vitro , biochemistry , cell culture , microbiology and biotechnology , cell growth , myristoylation , chemistry , biology , enzyme , peptide , prenylation , membrane , genetics
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 83:283–287, 1999. © 1999 Wiley‐Liss, Inc.