Potent, Cell Active, Non-Thiol Tetrapeptide Inhibitors of Farnesyltransferase

Hunt, John T.; Lee, Ving G.; Leftheris, Katerina; Seizinger, Bernd R.; Carboni, Joan M.; Mabus, John R.; Ricca, Carol; Yan, Ning; Manne, Veeraswamy

doi:10.1021/jm9507284

Cited by 92 publications

(49 citation statements)

References 25 publications

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“…B1088 (32) was provided by Dr. A. Garcia (Eisai Institute). BMS193269 (33) was provided by Dr. V. Manne (Bristol-Myers Squibb Co.). ␣-Hydroxyfarnesyl-phosphonic acid (34) was purchased from Sigma.…”

Section: Methodsmentioning

confidence: 99%

A Mutant Form of Human Protein Farnesyltransferase Exhibits Increased Resistance to Farnesyltransferase Inhibitors

Villar¹,

Urano²,

Guo³

et al. 1999

Journal of Biological Chemistry

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Protein farnesyltransferase (FTase) is a key enzyme responsible for the lipid modification of a large and important number of proteins including Ras. Recent demonstrations that inhibitors of this enzyme block the growth of a variety of human tumors point to the importance of this enzyme in human tumor formation. In this paper, we report that a mutant form of human FTase, Y361L, exhibits increased resistance to farnesyltransferase inhibitors, particularly a tricyclic compound, SCH56582, which is a competitive inhibitor of FTase with respect to the CAAX (where C is cysteine, A is an aliphatic amino acid, and X is the C-terminal residue that is preferentially serine, cysteine, methionine, glutamine or alanine) substrates. The Y361L mutant maintains FTase activity toward substrates ending with CIIS. However, the mutant also exhibits an increased affinity for peptides terminating with CIIL, a motif that is recognized by geranylgeranyltransferase I (GGTase I). The Y361L mutant also demonstrates activity with Ha-Ras and Cdc42Hs proteins, substrates of FTase and GGTase I, respectively. In addition, the Y361L mutant shows a marked sensitivity to a zinc chelator HPH-5 suggesting that the mutant has altered zinc coordination. These results demonstrate that a single amino acid change at a residue at the active site can lead to the generation of a mutant resistant to FTase inhibitors. Such a mutant may be valuable for the study of the effects of FTase inhibitors on tumor cells.Protein farnesyltransferase (FTase) 1 catalyzes the transfer of a farnesyl group onto a conserved cysteine residue four amino acids from the C terminus of a number of proteins, such as Ras, that are involved in cell growth and morphogenesis (1-4). This modification is critical for membrane association and subsequent protein-protein interactions of these proteins. FTase is a heterodimeric enzyme consisting of ␣-and ␤-subunits. The ␣-subunit of FTase is shared with the related prenyltransferase, protein geranylgeranyltransferase type I (GGTase I), whereas the ␤-subunits of FTase and GGTase I are approximately 30% homologous. The FTase enzyme recognizes the CAAX motif (C is cysteine, A is an aliphatic amino acid, and X is the C-terminal residue that is preferentially serine, cysteine, methionine, glutamine or alanine) that is found at the C termini of the substrate proteins. GGTase I enzyme also recognizes a CAAX motif; however, the terminal X amino acid is predominantly leucine or phenylalanine. This motif is referred to as the CAAL motif.The three-dimensional structures of the rat FTase enzyme have recently been resolved without substrate bound (5, 6), with bound substrate farnesyl pyrophosphate (FPP) (7), and with bound FPP and CAAX peptide analogs (8). In the structure without bound substrate, a non-cognate peptide provided by an adjacent ␤-subunit was modeled into the active site of the enzyme. The structure showed that the ␣-and ␤-subunits are largely composed of ␣-helices. The ␤-subunit forms a barrel-like structure, and one side of this barrel i...

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Section: Methodsmentioning

confidence: 99%

A Mutant Form of Human Protein Farnesyltransferase Exhibits Increased Resistance to Farnesyltransferase Inhibitors

Villar¹,

Urano²,

Guo³

et al. 1999

Journal of Biological Chemistry

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“…Most of these so-called non-thiol farnesyltransferase inhibitors have nitrogen-containing heterocycles, the ring nitrogen of which coordinates the enzyme-bound zinc, similarly to the cysteine thiol group [14]. However, it has been shown that nitrogen heterocycles can be replaced by aryl residues, which lack the ability to coordinate metal atoms, without Using docking studies of model compounds of nonthiol farnesyltransferase inhibitors as well as GRID analyses of the binding region of farnesyltransferase, we have located two different aryl binding clefts in the active site of farnesyltransferase, which we suggest to be the postulated aryl binding regions (Figure 1) [19].…”

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confidence: 99%

Non‐thiol Farnesyltransferase Inhibitors: Utilization of the Far Aryl Binding Site by 5‐Cinnamoylaminobenzophenones

Mitsch

Böhm

Sattler

et al. 2004

Archiv der Pharmazie

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“…The peptidomimetic inhibitors, BMS191563 (22) and B1088 (7), were provided by V. Manne (Bristol-Myers Squibb) and A.M. Garcia (Eisai Research Institute, Andover, MA), respectively. Another peptidomimetic inhibitor, FTI-277 (23), was provided by S. Sebti (University of South Florida) or purchased from Calbiochem.…”

mentioning

confidence: 99%

Farnesyltransferase inhibitors induce cytochrome c release and caspase 3 activation preferentially in transformed cells

Suzuki¹,

Urano²,

Tamanoi³

1998

Proc. Natl. Acad. Sci. U.S.A.

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Potent, Cell Active, Non-Thiol Tetrapeptide Inhibitors of Farnesyltransferase

Cited by 92 publications

References 25 publications

A Mutant Form of Human Protein Farnesyltransferase Exhibits Increased Resistance to Farnesyltransferase Inhibitors

A Mutant Form of Human Protein Farnesyltransferase Exhibits Increased Resistance to Farnesyltransferase Inhibitors

Non‐thiol Farnesyltransferase Inhibitors: Utilization of the Far Aryl Binding Site by 5‐Cinnamoylaminobenzophenones

Farnesyltransferase inhibitors induce cytochrome c release and caspase 3 activation preferentially in transformed cells

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