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Pre-clinical development of farnesyltransferase inhibitors

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Abstract

ras is the oncogene most frequently found in human cancers, being detected in 30% of most human cancers and at significantly higher rates in certain cancers including pancreatic (90%) and colon (50%) [1]. Almost 10 years ago it was shown that a C-terminal lipid modification of Ras, catalyzed by a specific farnesyl-protein transferase (FPTase), was required for the function of both normal and oncogenic Ras proteins. This finding spurred the development of FPTase inhibitors (FTIs) as a potential cancer therapy directed at the ras oncogene. FTIs have exhibited potent antiproliferative activity in cell culture and animal tumor models with a surprising lack of toxicity to normal tissues. However, while FTIs were originally conceptualized as Ras-specific agents, their mechanism of action is significantly more complicated than originally envisioned.

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Lobell, R.B., Kohl, N.E. Pre-clinical development of farnesyltransferase inhibitors. Cancer Metastasis Rev 17, 203–210 (1998). https://doi.org/10.1023/A:1006018922878

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