Design, synthesis and biological evaluation of peptidomimetic inhibitors of farnesyltransferase

Ras, a GTP-binding protein involved in cell growth and oncogenesis, undergoes post-translational modification in three steps, the first of which is the farnesylation of a cysteine residue, mediated by farnesyltransferase (FTase). Therefore, FTase inhibitors (FTis) have potential therapeutic indications. Here, we report a series of analogues of FTi 1, obtained by replacement of o-tolyl with other aromatic residues (compounds 2-7) and, moreover, of (2-amino-4-thiazolyl)methyl with 1,4-benzodioxan-2-yl (compounds 8-13), as well as their isopropyl esters 2a-13a. The effect on protein farnesylation was tested using a Ftase fluorescent assay and FTI-276 as a reference compound.