Farnesyltransferase as a target for anticancer drug design

Qian, Yimin; Sebti, Saı̈d M.; Hamilton, Andrew D.

doi:10.1002/(sici)1097-0282(1997)43:1<25::aid-bip4>3.0.co;2-2

Cited by 80 publications

(39 citation statements)

References 134 publications

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“…Several groups (ie natural product inhibitors, bisubstrate derivatives and peptidomimetics) of FTIs have been described and some of them seem to be very effective and well tolerated. 87,89 Peptide analogues were designed to inhibit FPTase activity on the basis of the last four amino acids of the Ras protein. These inhibitors have been reported to be very specific, since the minimal concentration at which they are effective is fairly low.…”

Section: Farnesyl Transferase Inhibitorsmentioning

confidence: 99%

Modulation of the immune response and tumor growth by activated Ras

Weijzen

Kast

1999

Leukemia

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As a result of its transforming abilities, activated Ras is expressed in a great number of cancers. The ras mutation frequency varies between 95% in pancreatic cancer and 5% in breast cancer. In leukemia, the highest frequency (30%) is found in acute myeloid leukemia. The presence of ras mutations has been correlated with a poor prognosis and negative clinical outcome. This suggests that mutated Ras activates mechanisms, which favor tumor growth, enhance the metastatic capacity of tumors or modulate tumor-specific immune responses. Several new functions of Ras, such as downregulation of major histocompatibility complex molecules, upregulation of certain cytokines, growth factors and degradative enzymes have been uncovered in the last decade. Additionally, mutated Ras can also serve as a primary target for the development of immunotherapy or drug therapy. This review will discuss the mechanisms by which Ras expressing tumors are able to evade destruction by the immune system and enhance their growth and metastatic potential. It will further elaborate on the attempts to develop successful immunotherapy and drug therapy targeting Ras expressing tumors.

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Section: Farnesyl Transferase Inhibitorsmentioning

confidence: 99%

Modulation of the immune response and tumor growth by activated Ras

Weijzen

Kast

1999

Leukemia

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“…Mimetics-A number of inhibitors of mammalian PFT have been developed over the past few years since such compounds are potentially useful as anticancer chemotherapeutics (63)(64)(65)(66). In this study we tested six CaaX mimetics as inhibitors of T. brucei PFT (Fig.…”

Section: Inhibition Of T Brucei Pft By Caaxmentioning

confidence: 99%

Protein Farnesyltransferase from Trypanosoma brucei

Yokoyama¹,

Trobridge²,

Buckner³

et al. 1998

Journal of Biological Chemistry

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We have previously shown that protein prenylation occurs in the Trypanosomatids Trypanosoma brucei (T. brucei), Trypanosoma cruzi, and Leishmania mexicana and that protein farnesyltransferase (PFT) activity can be detected in cytosolic extracts of insect (procyclic) form T. brucei. A PFT that transfers the farnesyl group from farnesyl pyrophosphate to a cysteine that is 4 residues upstream of the C terminus of the Ras GTP-binding protein RAS1-CVIM has now been purified 60,000-fold to near homogeneity from procyclic T. brucei. By screening a mixture of hexapeptides SSCALX (X is 20 different amino acids), it was found that SSCALM binds to T. brucei PFT with sub-micromolar affinity, and affinity chromatography using this peptide was a key step in the purification of this enzyme. On SDS-polyacrylamide gel electrophoresis, the enzyme migrates as a pair of bands with apparent molecular masses of 61 and 65 kDa, and thus its subunits are ϳ30% larger than those of the mammalian homolog. The 61-kDa band was identified as the putative ␤-subunit by photoaffinity labeling with a 32 P-labeled analog of farnesyl pyrophosphate. Mimetics of the C-terminal tetrapeptide of prenyl acceptors have been previously shown to inhibit mammalian PFT, and these compounds also inhibit T. brucei PFT with affinities in the nanomolar to micromolar range, although the structure-activity relationship is very different for parasite versus mammalian enzyme. Unlike mammalian cells, the growth of bloodstream T. brucei is completely inhibited by low micromolar concentrations of two of the PFT inhibitors, and these compounds also block protein farnesylation in cultured parasites. These compounds also potently block the growth of the intracellular (amastigote) form of T. cruzi grown in fibroblast host cells. The results suggest that protein farnesylation is a target for the development of anti-trypanosomatid chemotherapeutics.

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“…Due to the involvement of farnesylated proteins in carcinogenesis, inhibition of farnesyltransferase has received much interest in recent years [2][3][4][5] . Farnesyltransferase inhibitors have been demonstrated to inhibit a wide range of tumor cell lines in vitro and display synergistic effects with other tumor therapeutics [6][7][8] .…”

Section: Introductionmentioning

confidence: 90%