Studies on the synthesis and pharmacophore of farnesyl transferase inhibitor

Abstract

A promising method of interfering in Ras function involves inhibiting the enzyme farnesyltransferase (FTase), which modifies CaaX boxes of Ras and other proteins with the farnesyl pyrophosphate that is required for their correct cellular localization and biological activity. FTase inhibitors (FTIs) have demonstrated the potent and specific ability to block Ras processing, signaling and transformation in transformed and tumor cell lines in vitro and in selected animal models without toxicity to normal cells. Through structure-activity relationships (SARs) of FTIs and X-ray crystallographic data of the ternary complex (FTase-CaaX-FPP) repoted in many literatures, we proposed a pharmacophore model of bisubstrate FTI; zinc binding ligand, carboxylic acid, hydrophobic group Ⅰ (HG-Ⅰ) to block binding of FPP to FTase, hydrophobic group Ⅱ (HG-Ⅱ) to increase binding affinity to FTase and appropriate spacer connecting each pharmacophoric group. The binding sites of zinc ligand and carboxylic acid group were obvious from SARs reported in literatures. For confirming our pharmacophore model, initially tripeptide FTase inhibitors $(Ca_1a_2)$ which were methyl esters of CVS, CVY and CV-meta-Y with various hydrophobic groups at S, Y and meta-Y, related to HG-I, were designed, synthesized and evaluated for biological activity. $IC_{50}$ values of some compounds ($Y_4$, $Y_7$, $Ym_4$, $S_1$, $S_5$, $S_6$, $S_7$) were higher than that of the standard inhibitor CVFM-OMe. Through SARs of our inhibitors, we obtained one that the optimal size of the HG-I in $Ca_1a_2$ exists somewhere between benzyl and hexanoyl group. In addition, we investigated the peptidomimetics of above tripeptide with reduced amide of cystein, a rigid aromatic spacer and naphthyl group as HG-I $(N_2)$. $IC_{50}$ value of $N_2$ was 6.7 fold more potent than that of CVFM and this indicates that HG-I is more important than both HG-Ⅱ and carboxylic acid group. In order to understand whether the site of HG-Ⅱ exists ...