# Recent Advances in the Development of Mammalian Geranylgeranyl Diphosphate Synthase Inhibitors
## 2 Status and Nitrogenous Bisphosphonates  
The most widely used IBP-inhibiting drugs are statins for the treatment of hypercholesterolemia. Statins inhibit HMG-CoA reductase, which is well-recognized as the first committed step in isoprenoid biosynthesis. While statins do inhibit endogenous cholesterol biosynthesis, their cholesterol-lowering effects are secondary to increased clearance of LDL from the plasma due to upregulation of the hepatic LDL receptor [3; 4]. There is also evidence that statins influence cardiovascular health via other mechanisms, including putative effects on vascular inflammation, endothelial function and myocardial remodeling [5]. There has been considerable interest in the use of statins in other clinical indications, including cancer, neurological disorders, osteoporosis, asthma, coagulation, and thrombosis [6; 7; 8; 9; 10; 11]. The anti-cancer activities of statins appear related to their ability to disrupt protein prenylation [12]. The use of statins as anti-cancer agents in vivo, however, is likely to be limited. In vitro studies have demonstrated that the concentrations of statins required to affect prenylation are in the low micromolar range, while the concentrations needed to lower cholesterol biosynthesis are in the nanomolar range [13]. Standard dosing regimens result in serum drug levels of \(\sim\)0.1 \(\upmu\)M [14], thus it is likely that only cholesterol synthesis is impacted. Several phase I studies involving oncology patients have demonstrated that administration of high-dose statin can yield serum drug levels in the low micromolar range, however the higher doses were associated with side effects [15; 16]. These findings fueled investigation into the development of agents that inhibit downstream events in the IBP pathway as a means to inhibit protein prenylation more directly.  
Nitrogenous bisphosphates (NBPs) represent the second class of clinically used agents that target the IBP. Bisphosphonates can be viewed as non-hydrolysable analogues of pyrophosphate and their phosphorus-carbon-phosphorus backbone facilitates chelation of calcium ions. This results in a high affinity for bone, which ultimately leads to a high concentration in osteoclasts. In the clinic, NBPs are prescribed extensively for the treatment of osteoporosis and metastatic bone disease because they inhibit bone resorption. Interestingly, these agents were used clinically prior to an understanding of the molecular target. The first clue that NBPs may inhibit the IBP pathway came in the late 1990s when it was noted that NBPs disrupt protein prenylation [17; 18]. Further investigation revealed the enzyme FDPS as the target of NBPs [19; 20]. Inhibition of FDPS by NBPs depletes cells of both FPP and GGPP, thus disrupting all types of protein prenylation within a cell. NBPs effects on prenylation have been observed in a wide range of cell types, including macrophages, osteoclasts, osteoblasts, and endothelial cells, as well as various cancer cell lines. While anti-cancer activity has been observed in vitro, the benefit in vivo is likely substantially less given the limited systemic distribution of these drugs [21; 22; 23]. Despite this limitation, results from clinical trials suggest that the NBPs may provide therapeutic advantages that extend beyond skeletal-related events [21]. For instance, zoledronic acid is a potent FDPS inhibitor with an IC\({}_{50}\) of 3 nM [24]. A study in breast cancer patients found that zoledronic acid inhibited cellular proliferation and induced apoptosis when used as a monotherapy [25] and there is evidence in myeloma that zoledronic acid has treatment benefits beyond improving bone health [26].