Farnesyltransferase inhibitors
Section snippets
Farnesyltransferase
Farnesyltransferase is a member of a family of three enzymes responsible for protein prenylation.7 FTase attaches a 15-carbon lipid farnesyl, whereas geranylgeranyltransferase-I (GGTase-I) attaches a 20-carbon geranylgeranyl to the cysteine thiol group of proteins that end at their carboxyl terminal with the consensus sequence CAAX, where C is cysteine, A is an aliphatic or an aromatic residue, and X is any amino acid. FTase prefers X to be methionine or serine, whereas GGTase I prefers X to be
Chemistry
Two approaches have been taken to develop FTIs. One is based on rational design, using as a target the CAAX tetrapeptide. The other approach involves the random screening for FTase inhibition activity of either natural products or synthetic small-molecule libraries.2, 3, 4, 5, 6, 12 FTase recognizes and farnesylates tetrapeptides with the CAAX consensus sequence, and the tetrapeptides are potent competitive inhibitors of FTase with 50% inhibitory concentrations (IC50) of 20 to 200 nmol/L.13
Farnesyltransferase inhibitors interfere with mitosis by inhibiting bipolar spindle formation during prometaphase
The antitumor activity of FTIs in several animal models indicated that these compounds are antiproliferative and/or proapoptotic. Initial studies on the effects of FTIs on cell division and cell cycle progression demonstrated that FTI treatment resulted in accumulation in the G2/M phase in a number of human cancer cell lines. In other cancer cells, however, FTIs could either induce a G1 block or have no effect on cell cycle distribution.26 Whether FTIs block cells in G0/G1 appears to depend on
Suppression of the PI3K/Akt survival pathway is required for farnesyltransferase inhibitor-induced apoptosis in some human cancer cell lines
The tumor regression induced by FTIs in transgenic mice prompted many investigators in the field to evaluate the ability of FTIs to induce apoptosis. Lebowitz et al33 showed that FTIs can induce apoptosis but only when cells are deprived of substratum attachment. Suzuki et al34 found that attached cells can be induced to undergo apoptosis but only when deprived of serum. These studies suggested that adhesion and growth-factor pathways rescue cells from FTI-induced apoptosis. Jiang et al35
Inhibition of H-Ras farnesylation as a potential mechanism of farnesyltransferase inhibitor antitumor activity in some human cancers
The fact that FTIs are effective in some tumors but not in others preclinically as well as clinically (see below) indicates that farnesylated protein(s) are critical to survival and oncogenesis of some but not all human cancers.37 A major unresolved mechanistic issue in the field is that of identifying the farnesylated protein or proteins that play a critical role in malignant transformation of some human cancers. Because all four Ras proteins (H-, N-, KA-, and KB-Ras) require farnesylation to
Inhibition of RhoB farnesylation does not mediate farnesyltransferase inhibitor antitumor activity in human cancer cells
RhoB, a member of the Ras superfamily of low-molecular-weight GTPases, is a substrate for FTase and its farnesylation is inhibited by FTIs. However, RhoB is also geranylgeranylated by GGTase I, which makes its status as a target for FTI somewhat complex. Evidence for inhibition of RhoB as a mediator for FTI antitumor activity stems from the following observations. First, treatment of cells with FTIs results in decreased levels of RhoB-F and increased levels of RhoB-GG.42 Second, a RhoB/RhoA
Farnesyltransferase inhibitors in the clinic
Currently, three FTIs are in active clinical testing Table 1, Table 2. These agents belong to the nonthiol, nonpeptidomimetic heterocyclic class of small-molecule inhibitors. Two of these, lonafarnib (SCH66336) and tipifarnib (R115777), are orally bioavailable, whereas BMS-214662 is administered intravenously. Further clinical testing of another FTI, L-778,123, has been curtailed as a result of cardiac toxicity (QT prolongation), which is not seen with the other three agents. Contrary to
Farnesyltransferase inhibitors in chemoprevention
Because oncogenic ras may play an early role in the carcinogenic process, and in light of the relatively mild toxicity profile of the FTIs, these agents have been tested for their chemopreventive properties. A recent study was designed to test the efficacy of FTIs as potential chemopreventive compounds in a mouse lung tumor model and in tumor cell lines.80 This study showed that FTI-276 is chemopreventive in a primary mouse lung tumor model. Currently, a clinical study evaluating the
Conclusions
Recent reports of negative phase II and phase III trials of FTIs in colorectal cancer, pancreatic cancer, NSCLC, and SCLC have dampened enthusiasm somewhat for this novel class of agents. However, most of these earlier studies were based on the assumption that tumors with K-ras mutations will be sensitive to inhibition by FTIs. However, current data indicate that sensitivity to these agents is independent of ras mutational status, and that tumors with K-ras mutations are relatively more
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Dr Adjei has received research grant support from Bristol-Myers Squibb and Johnson and Johnson.