# Recent Advances in the Development of Mammalian Geranylgeranyl Diphosphate Synthase Inhibitors
## 3 GGDPS Inhibitors
Furthermore, the mixture was highly specific for GGDPS and displayed potent inhibition of protein geranylgeranylation in myeloma cells at concentrations as low as 30 nM [37; 40]. Subsequent preparation of the individual isomers allowed for comparisons between the two isomers and revealed that the homoneryl isomer is more potent than the homogeranyl [40; 45] (Table 1). Interestingly, however, there is evidence that the two isomers interact in a synergistic manner to inhibit GGDPS [40]. Computer modeling suggests that both isomers can bind simultaneously to GGDPS, with the homoneryl isomer binding preferentially at the FPP site and the homogeranyl isomer preferring the GGPP site of the enzyme [40]. Further studies are needed to explain why the synergistic interaction between the two olefin isomers is maximized when the two isomers are in a 3:1 homogeranyl:homoneryl ratio. This observation may be related to their individual affinity for the enzyme or to the oligomeric nature of GGDPS. Prior crystallography studies suggested that GGDPS assumes a hexameric organization composed of three dimers [46]. Regardless of the mechanism underlying the synergy, the homogeranyl/homoneryl triazoles represent a new paradigm in the development of GGDPS inhibitors. Further extension of the chain to a bishomogeranyl length abrogated activity, suggesting that the homogeranyl length is the optimal length for inhibitory activity in this motif [38] (Table 1). The observed activity of the bishomogeranyl/neryl series further confirmed the importance of olefin stereochemistry as the bishomoneryl triazole was noted to be more potent than the corresponding bishomogeranyl [38]. Finally, longer-chained derivatives, including farnesyl, homoframesyl, geranylgeranyl, and homogeranylgeranyl, have weak or no activity as GGDPS inhibitors (Table 1) [36; 41]. Figure 5: Stereoselective synthesis of isoprenoid triazole bisphosphonates through the use of epoxy azides [39]. A V-shaped dialkylated triazole bisphosphonate (**9**) containing homoprenyl and geranyl substituents did display inhibitory activity (IC\({}_{50}\) 0.38 uM) (Figure 2), but was less active than the mono-alkylated homogeranyl triazole [37]. While generation of more potent inhibitors remains a worthwhile pursuit, with highly charged compounds efforts to improve a drug's ability to cross the cell membranes are also critical. Preparation of a prodrug, which carries little or no charge, enables compounds to transit biological membranes, and then releases the parent drug once inside the target cell [47]. Preparation and testing of a series of pivaloyloxymethyl (POM)-modified mono- and dialkyl bisphosphonates revealed that the addition of the POM groups as protecting groups significantly increased the hydrophobicity and improved potency in a cellular geranylgeranylation assay by as much as 25-fold [48]. A second series of POM-prodrugs was reported by [PERSON] et al., that incorporated one isoprenoid chain on the \(\alpha\)-carbon, a second alkyl chain as a phosphonate ester, and the potential for a third alkyl chain at the \(\alpha\)-carbon [49]. Among the five bisphosphonates tested, the methyl derivative (**10**, Figure 2) was the most potent, with activity noted at 0.5 uM in cell assays. While the majority of published GGDPS inhibitors contain the bisphosphonate backbone, non-bisphosphonate inhibitors also have been described (**11**, Figure 2) [50]. These inhibitors had IC\({}_{50}\) values of \(\sim\)30-50 uM and consistently bound to the FPP or GGPP site of GGDPS. Despite their lower potency, the development of non-bisphosphonate compounds may still be of interest, as these compounds could have different peripheral distribution relative to bisphosphonate-based inhibitors. Finally, zwitterionic compounds based on phosphonium (**12**) and pyridinium (**13**) motifs have been reported that have dual activity against FDPS and GGDPS [51; 32].