Pre-clinical development of farnesyltransferase inhibitors.
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.
Department of Cancer Research, Merck Research Laboratories, West Point, USA.
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Lobell
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Kohl
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use*; D051231:Farnesyltranstransferase; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D018631:ras Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism
D004791:Enzyme Inhibitors; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase; D018631:ras Proteins