The Experts below are selected from a list of 1146 Experts worldwide ranked by ideXlab platform
George C Prendergast - One of the best experts on this subject based on the ideXlab platform.
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Farnesyltransferase Inhibitors mechanism and applications
Expert Opinion on Investigational Drugs, 2001Co-Authors: Neena Rane, George C PrendergastAbstract:Farnesyltransferase (FT) Inhibitors (FTIs) are among the first wave of signal transduction Inhibitors to be clinically tested for antitumour properties. FTIs were designed to attack Ras oncoproteins, the function of which depends upon post-translational modification by farnesyl isoprenoid. Extensive preclinical studies have demonstrated that FTIs compromise neoplastic transformation and tumour growth. In preclinical models, FTIs display limited effects on normal cell physiology and in Phase I human trials FTIs have been largely well tolerated. Exactly how FTIs selectively target cancer cells has emerged as an important question, one which has become more pressing with the somewhat disappointing results from initial Phase II efficacy trials. Although FTI development was predicated on Ras inhibition, it has become clear that the drugs’ antineoplastic properties are based to a large degree on altering the prenylation and function of proteins other than Ras. One key candidate that has emerged is RhoB, an endo...
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rhob is dispensable for mouse development but it modifies susceptibility to tumor formation as well as cell adhesion and growth factor signaling in transformed cells
Molecular and Cellular Biology, 2001Co-Authors: Aixue Liu, George C Prendergast, Neena Rane, Jehping LiuAbstract:RhoB is an endosomal small GTPase that is implicated in the response to growth factors, genotoxic stress, and Farnesyltransferase Inhibitors. To gain insight into its physiological functions we examined the consequences of homozygous gene deletion in the mouse. Loss of RhoB did not adversely affect mouse development, fertility, or wound healing. However, embryo fibroblasts cultured in vitro exhibited a defect in motility, suggesting that RhoB has a role in this process that is conditional on cell stress. Neoplastic transformation by adenovirus E1A and mutant Ras yielded differences in cell attachment and spreading that were not apparent in primary cells. In addition, transformed −/− cells displayed altered actin and proliferative responses to transforming growth factor β. A negative modifier role in transformation was suggested by the increased susceptibility of −/− mice to 7,12-dimethylbenz[a]anthracene-induced skin carcinogenesis and by the increased efficiency of intraperitoneal tumor formation by −/− cells. Our findings suggest that RhoB is a negative regulator of integrin and growth factor signals that are involved in neoplastic transformation and possibly other stress or disease states.
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rhob alteration is necessary for apoptotic and antineoplastic responses to Farnesyltransferase Inhibitors
Molecular and Cellular Biology, 2000Co-Authors: Aixue Liu, George C Prendergast, Jehping Liu, Thomas M JessellAbstract:Farnesyltransferase Inhibitors (FTIs) are in clinical trials, but how they selectively inhibit malignant cell growth remains uncertain. One important player in this process appears to be RhoB, an endosomal Rho protein that regulates receptor trafficking. FTI treatment elicits a gain of the geranylgeranylated RhoB isoform (RhoB-GG) that occurs due to modification of RhoB by geranylgeranyltransferase I in drug-treated cells. Notably, this event is sufficient to mediate antineoplastic effects in murine models and human carcinoma cells. To further assess this gain-of-function mechanism and determine whether RhoB-GG has a necessary role in drug action, we examined the FTI response of murine fibroblasts that cannot express RhoB-GG due to homozygous deletion of the rhoB gene. Nullizygous (-/-) cells were susceptible to cotransformation by adenovirus E1A plus activated H-Ras but defective in their FTI response, despite complete inhibition of H-Ras prenylation. Actin cytoskeletal and phenotypic events were disrupted in -/- cells, implicating RhoB-GG in these effects. Interestingly, -/- cells were resistant to FTI-induced growth inhibition under anchorage-dependent but not anchorage-independent conditions, indicating that, while RhoB-GG is sufficient, it is not necessary for growth inhibition under all conditions. In contrast, -/- cells were resistant to FTI-induced apoptosis in vitro and in vivo. Significantly, the apoptotic defect of -/- cells compromised the antitumor efficacy of FTI in xenograft assays. This study offers genetic proof of the hypothesis that RhoB-GG is a crucial mediator of the antineoplastic effects of FTIs.
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geranylgeranylated rhob mediates suppression of human tumor cell growth by Farnesyltransferase Inhibitors
Cancer Research, 1999Co-Authors: George C PrendergastAbstract:Farnesyltransferase Inhibitors (FTIs) are in clinical trials, but their mechanism of action is not fully understood. We have shown that FTI treatment rapidly elevates the level of geranylgeranylated RhoB in cells and that this event is sufficient to inhibit cell cycle transit and reverse malignant transformation without affecting normal cells. However, because these observations were made in rodent fibroblast models in which transformation was driven by defined genetic alterations, it remained to be established whether RhoB-GG was relevant to the antineoplastic effects of FTIs in human epithelial tumor cells with diverse genetic backgrounds. In this study, we show that elevated levels of RhoB-GG are sufficient to block the proliferation of FTI-sensitive but not FTI-resistant human carcinoma cells. RhoB-GG induced the cell cycle kinase inhibitor p21 WAF1 in a p53-dependent manner, similar to FTI treatment, but this event was dispensable because RhoB-GG could still inhibit the growth of p53-null cells that lacked p21 WAF1 activation. Consistent with actions beyond G 1 -phase arrest, certain cell lines exhibited accumulation in G 2 -M phase or an increased apoptotic index in response to RhoB-GG. We concluded that RhoB-GG suppressed human tumor cell proliferation by more than one mechanism and that it promoted apoptosis as well as inhibited cell cycle transit in malignant epithelial cells. These findings suggest how FTIs suppress the growth of human tumor cells that lack Ras mutations.
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cell growth inhibition by Farnesyltransferase Inhibitors is mediated by gain of geranylgeranylated rhob
Molecular and Cellular Biology, 1999Co-Authors: Peter F Lebowitz, George C PrendergastAbstract:Recent results have shown that the ability of Farnesyltransferase Inhibitors (FTIs) to inhibit malignant cell transformation and Ras prenylation can be separated. We proposed previously that farnesylated Rho proteins are important targets for alternation by FTIs, based on studies of RhoB (the FTI-Rho hypothesis). Cells treated with FTIs exhibit a loss of farnesylated RhoB but a gain of geranylgeranylated RhoB (RhoB-GG), which is associated with loss of growth-promoting activity. In this study, we tested whether the gain of RhoB-GG elicited by FTI treatment was sufficient to mediate FTI-induced cell growth inhibition. In support of this hypothesis, when expressed in Ras-transformed cells RhoB-GG induced phenotypic reversion, cell growth inhibition, and activation of the cell cycle kinase inhibitor p21WAF1. RhoB-GG did not affect the phenotype or growth of normal cells. These effects were similar to FTI treatment insofar as they were all induced in transformed cells but not in normal cells. RhoB-GG did not promote anoikis of Ras-transformed cells, implying that this response to FTIs involves loss-of-function effects. Our findings corroborate the FTI-Rho hypothesis and demonstrate that gain-of-function effects on Rho are part of the drug mechanism. Gain of RhoB-GG may explain how FTIs inhibit the growth of human tumor cells that lack Ras mutations.
Martin Schlitzer - One of the best experts on this subject based on the ideXlab platform.
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non thiol Farnesyltransferase Inhibitors n 4 acylamino 3 benzoylphenyl 3 5 4 nitrophenyl 2 furyl acrylic acid amides
Bioorganic & Medicinal Chemistry, 2003Co-Authors: Katja Kettler, Jacek Sakowski, Katrin Silber, Isabel Sattler, G Klebe, Martin SchlitzerAbstract:We have designed the nitrophenylfurylacryl-substituted benzophenone 4f as a non-thiol Farnesyltransferase inhibitor utilizing a novel aryl binding site of Farnesyltransferase. Variation of the 2-acylamino substituent at the benzophenone core structure of our initial lead 4f yielded several non-thiol Farnesyltransferase Inhibitors with improved activity. These compounds display activity in the low nanomolar range.
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non thiol Farnesyltransferase Inhibitors n 4 acylamino 3 benzoylphenyl 4 nitrocinnamic acid amides
Bioorganic & Medicinal Chemistry, 2002Co-Authors: Jacek Sakowski, Isabel Sattler, Martin SchlitzerAbstract:Abstract We have developed the 4-nitrocinnamoyl substituted benzophenone 4a as a novel non-thiol Farnesyltransferase inhibitor. Replacement of the p -tolyl moiety of our initial lead structure 4a by different para and ortho substituted phenyl residues as well as by 1-naphthyl resulted in derivatives with considerably enhanced activity displaying IC 50 values between 42 and 52 nM. These compounds represent novel, readily accessible non-thiol Farnesyltransferase Inhibitors being more active than the corresponding thiol-containing analogues.
Christophe Dardonville - One of the best experts on this subject based on the ideXlab platform.
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Recent advances in antitrypanosomal chemotherapy: patent literature 2002–2005. Expert
2016Co-Authors: Christophe DardonvilleAbstract:Sleeping sickness and Chagas ’ disease (African and American trypanosomiases, respectively) are protozoan parasitic diseases threatening millions of people in sub-Saharan Africa and Latin America, respectively. Trypanosomiases are among the most neglected diseases in the world, lacking desperately from financial support for investigation. The current chemotherapy of both diseases is poor and suffers from intolerable side-effects and low efficacy in many cases. A review of the patent literature (2002-early 2005) claiming for molecules with antitrypanosomal activity afforded 36 entries, equally shared between industry and academia. Among the targets validated against trypanosomes, patents dealing with proteases Inhibitors were the most represented (16 patents). Other targets claimed in the patent literature included membrane architecture (sterol biosynthesis Inhibitors, protein Farnesyltransferase Inhibitors), DNA (DNA binders, tubulin Inhibitors) and pyrimidine metabolism (CTP synthetase Inhibitors). Natural products were also a great source of trypanocidal lead compounds (9 patents). A few patents claiming for compounds with antitrypanosoma
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recent advances in antitrypanosomal chemotherapy patent literature 2002 2004
Expert Opinion on Therapeutic Patents, 2005Co-Authors: Christophe DardonvilleAbstract:Sleeping sickness and Chagas disease (African and American trypanosomiases, respectively) are protozoan parasitic diseases threatening millions of people in sub-Saharan Africa and Latin America. Trypanosomiases are among the most neglected diseases in the world, desperately lacking financial support for investigation. The current chemotherapy of both diseases is poor and suffers from intolerable side effects and low efficacy in many cases. A review of the patent literature from 2002 to early 2005 claiming molecules with antitrypanosomal activity afforded 36 entries, equally shared between industry and acadaemia. Among the targets validated against trypanosomes, patents dealing with protease Inhibitors were the most represented (16 patents). Other targets claimed in the patent literature included membrane architecture (sterol biosynthesis Inhibitors, protein Farnesyltransferase Inhibitors), DNA (DNA binders, tubulin Inhibitors) and pyrimidine metabolism (cytidine triphosphate [CTP] synthetase Inhibitors). ...
Kevan M Shokat - One of the best experts on this subject based on the ideXlab platform.
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Farnesyltransferase mediated delivery of a covalent inhibitor overcomes alternative prenylation to mislocalize k ras
ACS Chemical Biology, 2017Co-Authors: Chris J Novotny, Gregory Hamilton, Frank Mccormick, Kevan M ShokatAbstract:Mutationally activated Ras is one of the most common oncogenic drivers found across all malignancies, and its selective inhibition has long been a goal in both pharma and academia. One of the oldest and most validated methods to inhibit overactive Ras signaling is by interfering with its post-translational processing and subsequent cellular localization. Previous attempts to target Ras processing led to the development of Farnesyltransferase Inhibitors, which can inhibit H-Ras localization but not K-Ras due to its ability to bypass farnesyltransterase inhibition through alternative prenylation by geranylgeranyltransferase. Here, we present the creation of a neo-substrate for Farnesyltransferase that prevents the alternative prenlation by geranylgeranyltransferase and mislocalizes oncogenic K-Ras in cells.
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Farnesyltransferase-Mediated Delivery of a Covalent Inhibitor Overcomes Alternative Prenylation to Mislocalize K‑Ras
2017Co-Authors: Chris J. Novotny, Frank Mccormick, Gregory L. Hamilton, Kevan M ShokatAbstract:Mutationally activated Ras is one of the most common oncogenic drivers found across all malignancies, and its selective inhibition has long been a goal in both pharma and academia. One of the oldest and most validated methods to inhibit overactive Ras signaling is by interfering with its post-translational processing and subsequent cellular localization. Previous attempts to target Ras processing led to the development of Farnesyltransferase Inhibitors, which can inhibit H-Ras localization but not K-Ras due to its ability to bypass farnesyltransterase inhibition through alternative prenylation by geranylgeranyltransferase. Here, we present the creation of a neo-substrate for Farnesyltransferase that prevents the alternative prenlation by geranylgeranyltransferase and mislocalizes oncogenic K-Ras in cells
Said M. Sebti - One of the best experts on this subject based on the ideXlab platform.
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phase ii study of the Farnesyltransferase inhibitor r115777 in advanced melanoma calgb 500104
Journal of Translational Medicine, 2012Co-Authors: Thomas F Gajewski, Michelle A Blaskovich, Said M. Sebti, April K S Salama, Donna Niedzwiecki, Jeffrey L Johnson, Gerald P Linette, Cynthia Bucher, Frank G HaluskaAbstract:Background Multiple farnesylated proteins are involved in signal transduction in cancer. Farnesyltransferase Inhibitors (FTIs) have been developed as a strategy to inhibit the function of these proteins. As FTIs inhibit proliferation of melanoma cell lines, we undertook a study to assess the impact of a FTI in advanced melanoma. As farnesylated proteins are also important for T cell activation, measurement of effects on T cell function was also pursued.
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protein farnesylation implications for normal physiology malignant transformation and cancer therapy
Cancer Cell, 2005Co-Authors: Said M. SebtiAbstract:Protein farnesylation is a lipid posttranslational modification required for the cancer-causing activity of proteins such as the GTPase Ras. Although Farnesyltransferase Inhibitors (FTIs) are in clinical trials, their mechanism of action and the role of protein farnesylation in normal physiology are ill understood. In this issue of Cancer Cell, two articles shed light on these important issues. Protein farnesylation was found to be essential for early embryogenesis, dispensable for adult homeostasis, and critical for progression but not initiation of tumorigenesis. Furthermore, Rab geranylgeranyltransferase was identified as a target for some FTIs. This minireview discusses the implications of these findings on normal physiology, malignant transformation, and cancer therapy.
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searching for the elusive targets of Farnesyltransferase Inhibitors
Nature Reviews Cancer, 2003Co-Authors: Said M. Sebti, Channing J DerAbstract:Farnesyltransferase (FTase) Inhibitors (FTIs) were developed originally as anti-RAS compounds and novel target-based drugs for cancer treatment. The analyses of FTIs continue in the clinic, but the antitumour activity cannot be ascribed simply to inhibition of RAS. Although FTI action is due to inhibition of FTase, and RAS proteins are indeed substrates for this enzyme, the RAS proteins that are most frequently mutated in human cancers escape FTI inhibition. RHOB has been suggested as a target, but is this issue resolved or do the crucial targets of FTIs remain to be identified?
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Farnesyltransferase Inhibitors are potent lung cancer chemopreventive agents in a j mice with a dominant negative p53 and or heterozygous deletion of ink4a arf
Oncogene, 2003Co-Authors: Zhongqiu Zhang, Said M. Sebti, Ronald A Lubet, Yian Wang, Laura E Lantry, Elizabeth Kastens, Gongjie Liu, A Hamilton, Ming YouAbstract:Mutations in the Kras2 gene are seen in both human and mouse lung adenocarcinomas. The protein product (p21ras) encoded by the Kras2 gene must be post-translationally modified at a terminal CAAX motif in order to be biologically active. In this study, we systematically investigated the chemopreventive efficacy of two different Farnesyltransferase Inhibitors (FTIs): one is a peptidomimetic (FTI-276) and the other is an imidazole (L778-123). Both FTIs are designed to inhibit the post-translational modification of p21ras proteins with a terminal CAAX motif. In a complete chemoprevention study, where the inhibitor was administered before carcinogen was given, and throughout the study, FTI-276 treatment significantly reduced both the tumor multiplicity by 41.7% (P<0.005), and the total tumor volume by 79.4% (P<0.0001). In the late treatment study, where mice were treated with an inhibitor 12 to 20 weeks after carcinogen administration, FTI-276 treatment resulted in a 60% reduction in tumor multiplicity and 58% reduction in tumor volume. Next, we examined the chemopreventive efficacy of a new FTI, L-778,123, on lung tumor development in A/J mice and transgenic mice with a dominant-negative p53 mutation and/or heterozygous deletion of Ink4a/Arf. Treatment of mice with L-778,123 for a period of 10 weeks from 20 weeks to 30 weeks post carcinogen initiation resulted in an approximately 50% decrease in tumor multiplicity in wild-type mice and mice with a dominant-negative p53 mutation and/or heterozygous deletion of the Ink4a/Arf tumor suppressor genes. Interestingly, tumor volume was decreased approximately 50% in wild-type mice and in mice with an Ink4a/Arf heterozygous deletion, while tumor volume was decreased approximately 75% in animals with a dominant-negative p53 and in mice with both a p53 mutation and heterozygous deletion of Ink4a/Arf. This result suggests that FTI exhibited a significantly (P<0.05) more efficacious chemopreventive effect in animals with alterations of p53 and Ink4a/Arf as contrasted with wild-type mice. Thus, FTIs are potent lung chemopreventive agents in both A/J mice and transgenic mice harboring a dominant-negative p53 and heterozygous deletion of Ink4a/Arf. In fact, L-778,123 is more effective in inhibiting primary lung progression in mice with a p53 mutation and/or an Ink4a/Arf deletion than in wild-type animals.
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Farnesyltransferase Inhibitors potentiate the antitumor effect of radiation on a human tumor xenograft expressing activated hras
Radiation Research, 2000Co-Authors: Elizabeth Cohenjonathan, Said M. Sebti, Andrew D Hamilton, Ruth J Muschel, Gillies W Mckenna, Sydney M Evans, George J Cerniglia, Rosemarie Mick, Donna Kusewitt, Allen OliffAbstract:Abstract Cohen-Jonathan, E., Muschel, R. J., McKenna, W. G., Evans, S. M., Cerniglia, G., Mick, R., Kusewitt, D., Sebti, S. M., Hamilton, A. D., Oliff, A., Kohl, N., Gibbs, J. B. and Bernhard, E. J. Farnesyltransferase Inhibitors Potentiate the Antitumor Effect of Radiation on a Human Tumor Xenograft Expressing Activated HRAS. Successful radiosensitization requires that tumor cells become more radiosensitive without causing an equivalent reduction in the survival of cells of the surrounding normal tissues. Since tumor cell radiosensitivity can be influenced by RAS oncogene activation, we have hypothesized that inhibition of oncogenic RAS activity would lead to radiosensitization of tumors with activated RAS. We previously showed in tissue culture that prenyltransferase treatment of cells with activated RAS resulted in radiosensitization, whereas treatment of cells with wild-type RAS had no effect on radiation survival. Here we ask whether the findings obtained in vitro have applicability in vivo. We found...
