Inhibitor SourceBook™ Second Edition

Other Inhibitors of Biological Interest
Inhibitors of Farnesyltransferase (FTase), Geranylgeranyltransferase
(GGTase), and Methyltransferase
Prenylation is carried out by cytoplasmic enzymes
known as geranylgeranyltransferases and
farnesyltransferases that covalently attach 20-carbon
(geranylgeranyl) or 15-carbon (farnesyl) isoprenoids to
the C-terminus of intracellular proteins via thioether
linkages. Protein farnesyltransferase I (FTase I) and
protein geranylgeranyltransferase I (GGTase I) recognize
a CAAX motif as substrate, where C is cysteine, A
represents any aliphatic amino acid, and X is either
serine or methionine (FTase I), or leucine (GGTase I).
The Rab GGTase II attaches geranylgeranyl groups to
proteins that terminate in either CC or CXC motifs. Many
proteins in signal transduction pathways are prenylated.
Perhaps the best-characterized farnesylation products
are the Ras ATPases. Ras is a guanine nucleotide binding
protein that transduces growth and differentiation
signals from receptor tyrosine kinases to the nucleus.
Mammalian cells express four types of Ras; H-, N-,
KA-, and KB-Ras. Mutated or oncogenic forms of Ras
require farnesylation for their ability to transform cells.
Peptidomimetics designed against the Ras CAAX motif
have been shown to reverse oncogenic transformation
by H-Ras and inhibit growth of H-Ras-transformed
cells. Hence, several types of FTase inhibitors have been
designed for use as potential anticancer agents. Since
Ras proteins are posttranslationally modified by FTase
and carboxymethylation and they act as a common focal
point for signals from growth factor receptors, use of
FTase inhibitors is likely to interfere with their action
and impede cell proliferation. These inhibitors can be
divided into four groups based on the mechanism of
their action: (1) competitive inhibitors of farnesyl PPi, (2)
peptidomimetic inhibitors based on the CAAX motif, (3)
bisubstrate inhibitors, and (4) inhibitors with unknown
mechanisms. CAAX peptidomimetics can either
function as alternative substrates in the FTase catalyzed
reaction, or they can competitively inhibit FTase without
serving as substrates.
References:
Mazieres, J., et al. 2004. Cancer Lett. 206, 59.
Sebti, S.M., and Adjei, A.A. 2004. Semin. Oncol. 31 (Suppl ), 28.
Head, J.E., and Johnston, S.R. 2003. Expert Opin. Emerg. Drugs 8, 63.
Casey, P.J., and Seabra, M.C. 996. J. Biol. Chem. 271, 5289.
Lerner, E.C., et al. 995. J. Biol. Chem. 270, 26802.
Kelloff, G.J., et al. 997. Cancer Epidemiol. Biomarkers Prev. 6, 267.
Product Cat. No. Comments Size Price
N-Acetyl-S-farnesyl-L-cysteine
(AFC)
N-Acetyl-S-geranylgeranyl-Lcysteine
(AGGC)
More online... www.calbiochem.com/inhibitors/Ftase
Inhibitors of Farnesyltrasferase (FTase), Geranylgeranyltransferase (GGTase), and Methyltransferase
110110 (AFC)
Exhibits high affinity for S-farnesyl-cysteine methyltransferase
(K m = 20 mM) and thereby inhibits the COOH-terminal methylation
of proteins in intact cells as well as in cell-free systems. Also inhibits
fMLP-induced superoxide anion generation (IC 50 = 5 mM).
110115 (AGGC)
Exhibits higher affinity (K m = 7 mM) than AFC for carboxyl methyltransferase
and acts as a more effective inhibitor of fMLP-induced
superoxide anion generation (IC 50 = 4 mM) than AFC.
5'-Deoxy-5'-methylthioadenosine 260585 (MeSAdo; MTA)
Potently inhibits protein carboxymethyltransferase and induces
apoptosis in leukemia U937 cells.
FPT Inhibitor I 344150 {(E,E)-2-[(Dihydroxyphosphinyl)methyl]-3-oxo-3-[(3,7,11-trimethyl-
2,6,10-dodecatrienyl)-amino]propanoic Acid, 3Na}
A highly selective and potent inhibitor of Ras farnesyl-protein
transferase (IC 50 = 83 nM). At much higher concentrations, inhibits
geranylgeranyltransferase I (IC 50 = 26 mM) and II (IC 50 = 47 mM).
Resistant to cleavage by phosphatases.
5 mg $92
5 mg $92
50 mg $73
mg $89
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