CAAX Peptidomimetic FTI-244 Decreases Platelet-Derived Growth Factor Receptor Tyrosine Phosphorylation Levels and Inhibits Stimulation of Phosphatidylinositol 3-Kinase but Not Mitogen-Activated Protein Kinase

McGuire, Terence F.; Qian, Yimin; Blaskovich, Michelle A.; Fossum, Renae D.; Sun, Jiazhi; Marlowe, Tara; Corey, Seth J.; Wathen, Steven P.; Vogt, Andreas; Hamilton, Andrew D.; Sebti, Saı̈d M.

doi:10.1006/bbrc.1995.2287

Cited by 16 publications

(3 citation statements)

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“…2). However, subsequent studies helped to demonstrate that the -turn conformation was actually not required for FTase inhibition [149,150], a conclusion that was further strengthened by more recent crystallographic studies which disclosed a preference for an extended conformation in FTase-bound CAAX peptides [128].…”

Section: Peptide Analoguesmentioning

confidence: 93%

Farnesyltransferase Inhibitors: A Detailed Chemical View on an Elusive Biological Problem

Sousa

Fernandes²,

Ramos³

2008

CMC

108

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Farnesyltransferase (FTase) is a zinc enzyme that has been the subject of particular attention in anti-cancer research. This enzyme promotes the addition of a farnesyl group from farnesyl diphosphate (FPP) to a cysteine residue of a protein substrate containing a typical -CAAX motif at the carboxyl terminus. Initial interest in FTase inhibition was prompted by the finding that farnesylation was absolutely required for the oncogenic forms of ras proteins to transform cells, as ras proteins have been implicated in around 30% of all human cancers. This discovery led to frenetic search for FTase inhibitors (FTIs), with more than 400 patents registered in less than a decade. However, despite the very promising initial results, the outcome of Phase II and Phase III clinical trials was, is general, rather disappointing, with the most advanced FTIs failing to demonstrate anti-tumor activity in ras dependent cancers, presumably because K-ras, the most frequently mutated form of ras in human cancers, is able to bypass FTI blockade through cross-prenylation by the related enzyme geranylgeranyltransferase I (GGTase I). Surprisingly, several of these compounds were later shown to have anti-tumor activity against non-ras dependent cancers, launching the grounds for a new and exciting era in FTIs research and development, although the precise target for the FTIs activity of these compounds still remains unknown. This review reports the recent progress in the field, presenting a comprehensive summary of the most promising FTIs, in terms of their chemical structure and properties, taking into account the topology of the enzyme's active-site, and the most recent mechanistic results on the catalytic activity of FTase, both at the theoretical and mechanistic level. These features are presented in close linking with the available results on the biological activity of these inhibitors, and with the outcome of the most recent clinical trials.

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Section: Peptide Analoguesmentioning

confidence: 93%

Farnesyltransferase Inhibitors: A Detailed Chemical View on an Elusive Biological Problem

Sousa

Fernandes²,

Ramos³

2008

CMC

108

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“…We have used this protocol to evaluate CaaX peptidomimetics 85,86 , non-peptide Ras-CaaX mimetics 87 , FTI-244 (ref. 88), FTI 276/277 and GGTI-286/287 (refs. 47, 89), whereas others have used the same or similar assays to characterize the potency and specificity of the FTIs Lonafarnib 66 and BMS-214662 (ref.…”

Section: Introductionmentioning

confidence: 99%

Measurement of protein farnesylation and geranylgeranylation in vitro, in cultured cells and in biopsies, and the effects of prenyl transferase inhibitors

Berndt

Sebti

2011

Nat Protoc

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The importance of the post-translational lipid modifications farnesylation and geranylgeranylation in protein localization and function coupled with the critical role of prenylated proteins in malignant transformation has prompted interest in their biology and the development of farnesyl transferase and geranylgeranyl transferase inhibitors (FTIs and GGTIs) as chemical probes and anticancer agents. The ability to measure protein prenylation before and after FTI and GGTI treatment is important to understanding and interpreting the effects of these agents on signal transduction pathways and cellular phenotypes, as well as to the use of prenylation as a biomarker. Here we describe protocols to measure the degree of protein prenylation by farnesyl transferase or geranylgeranyl transferase in vitro, in cultured cells and in tumors from animals and humans. The assays use [3H]farnesyl diphosphate and [3H]geranylgeranyl diphosphate, electrophoretic mobility shift, membrane association using subcellular fractionation or immunofluorescence of intact cells, [3H]mevalonic acid labeling, followed by immunoprecipitation and SDS-PAGE, and in vitro transcription, translation and prenylation in reticulocyte lysates. These protocols require from 1 day (enzyme assays) to up to 3 months (autoradiography of [3H]-labeled proteins).

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“…Several isoprenylated proteins, including Ras (substrate of FPTase), RhoA and Rac1 (both are substrates of type I GGPTase), have been shown to have transforming properties (14)(15)(16). At least in the case of Ras, isoprenylation is required for its transforming activity (17,18), and inhibitors of FPTase have been shown to alter signal transductions (19,20), revert the ras-induced transforming phenotype in tissue culture models (21)(22)(23), and inhibit the growth or cause the regression of ras-related tumors in animal models (24)(25)(26).…”

Section: Introductionmentioning

confidence: 99%

Modulation of small G protein isoprenylation by anticancer monoterpenes in in situ mammary gland epithelial cells

Ren

Gould

1998

Carcinogenesis

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Monoterpenes have been shown to both prevent and treat mammary cancer in animal models and are currently in clinical testing in advanced cancer patients. In this study, we investigated a biochemical modulation associated with the antitumor activity of monoterpenes, the inhibition of protein isoprenylation in monoterpene chemoprevention target tissue, i.e. the in situ mammary gland epithelial cells. We first developed a new methodology that for the first time permitted the study of protein isoprenylation and other products in the mevalonate pathway in in situ mammary cells. Using this approach, we found that chronically feeding rats with an anticancer dose of perillyl alcohol resulted in a 22% inhibition of coenzyme Q synthesis and a 19% inhibition of small G protein isoprenylation in mammary gland epithelial cells in situ. The greatest inhibition of small G protein isoprenylation observed was the 28% inhibition of isoprenylation of RhoA by type I geranylgeranyl protein transferase (GGPTase). Given that some substrates of type I GGPTase, such as RhoA and Rac1, have transforming properties, the possibility that the inhibition of type I GGPTase will change the cellular location and functionality of these proteins and thus contribute to the chemoprevention activity of monoterpenes, is discussed.

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CAAX Peptidomimetic FTI-244 Decreases Platelet-Derived Growth Factor Receptor Tyrosine Phosphorylation Levels and Inhibits Stimulation of Phosphatidylinositol 3-Kinase but Not Mitogen-Activated Protein Kinase

Cited by 16 publications

References 0 publications

Farnesyltransferase Inhibitors: A Detailed Chemical View on an Elusive Biological Problem

Farnesyltransferase Inhibitors: A Detailed Chemical View on an Elusive Biological Problem

Measurement of protein farnesylation and geranylgeranylation in vitro, in cultured cells and in biopsies, and the effects of prenyl transferase inhibitors

Modulation of small G protein isoprenylation by anticancer monoterpenes in in situ mammary gland epithelial cells

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