Inhibition of farnesylated proteins such as RheB or CENP E appears to be among the consolidated data for some non Ras tumors selleck compound sensitive to FTIs. Complicating this pic ture, recent data suggest that farnesylation independent pathways might also participate in the anticancer activity of FTIs. Despite this lack of knowledge, the low toxicity of FTIs for normal cells and their wide range of high anti proliferative Inhibitors,Modulators,Libraries action on tumor cells led to the introduc tion of orally available Inhibitors,Modulators,Libraries FTI molecules into clinical trials. The FTI Tipifarnib has been evaluated for the treatment of myeloid malignancy, including for elderly patients with acute myelogenous leukemia. Moreover, Tipifarnib has shown promising results in coadjutant therapies for breast can cer.

The FTI Lonafarnib have shown efficacy in melanoma cells that develop resistance to Sorafenib, a pan Raf inhibitor. The poor Inhibitors,Modulators,Libraries performance of FTIs at the clinical level compared to their anticipated wide use in anticancer therapy clearly shows the weakness of the mechanistic studies performed thus far. The further ex ploitation and future introduction of FTIs into clinical therapy will largely depend on the identification of com pounds that increase FTI antiproliferative action in re sistant tumors and on the identification of susceptibility prediction markers. The major limitation of proteomic approaches under taken thus far devoted to clarifying which farnesylated proteins are differentially prenylated upon FTI treatment has been the difficulty of correlating the effective protein prenylation status with their anti proliferative action.

Several Inhibitors,Modulators,Libraries types of genomic technologies have been used to identify predictive markers pathways that could explain how FTIs affect cellular activity and responsive ness. A handful of genes has been identified whose func tion might lead to FTI resistance. Lack of FTI responsiveness has been shown to result from innate or acquired resistance or from FTI mediated activation of pro survival pathways. In addition, mutation of FTase or target genes, activation of alternative prenylation pathways, or changes in the balance of prenylated proteins have been described extensively upon FTI treatment. To identify the major protein networks responding to FTI peptidomimetics as well as the major pathways that allow an escape from Inhibitors,Modulators,Libraries the anti proliferative selleck chemical Temsirolimus action of FTIs in yeast and mammalian tumor cell lines, we used bud ding yeast cell based omic approaches and then vali dated the main findings in mammalian cancer cell lines. Well characterized structurally related FTI compounds that are active in yeast or in mammalian cells, FTase in hibitor I and FTI 277, respectively, were used in order to compare the data.