Farnesyltransferase inhibitors: mechanism and applications

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Abstract
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 endosomal protein that has been implicated in selective growth inhibition and apoptosis in neoplastic cells. On the basis of mechanistic studies and other recent developments, we propose that FTIs may be useful to treat a unique spectrum of diseases including not only inflammatory breast cancer and melanoma but also non-neoplastic diseases such as diabetic retinopathy and macular degeneration.