# Recent Advances in the Development of Mammalian Geranylgeranyl Diphosphate Synthase Inhibitors
## 1 Introduction  
The isoprenoid biosynthetic pathway (IBP) is one of the most heavily targeted biochemical pathways in medicine, with millions of individuals currently taking statins to lower cholesterol levels or nitrogenous bisphosphonates to address bone disease. Entry into the mammalian IBP begins when HMG-CoA reductase (HMGR) converts 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) to mevalonate via the rate-limiting step in the pathway (Figure 1). Mevalonate is phosphorylated and then decarboxylated to yield isoprenenyl pyrophosphate (IPP), which can reversibly isomerize to dimethylallyl pyrophosphate (DMAPP). Both DMAPP and IPP serve as substrates for farnesyl diphosphate synthase (FDPS) which generates first the 10-carbon geranyl pyrophosphate (GPP) and then the 15-carbon farnesyl pyrophosphate (FPP). In a reaction mediated by the enzyme geranylgeranyl diphosphate synthase (GGDPS), FPP and IPP are condensed to yield the 20-carbon compound geranylgeranyl diphosphate (GGPP).  
Two key products of the IBP, FPP and GGPP (**1** and **2**, Figure 2), serve as substrates for farnesyl transferase (FTase) and geranylgeranyltransferases (GGTase I and II), respectively. These enzymes play a critical role in the posttranslational modification of the Ras small GTPase superfamily of proteins (e.g., Ras, Rab, and Rho families). Prenylation refers to the addition of a 15-carbon isoprenoid chain (via farnesylation) or a 20-carbon isoprenoid chain (via geranylgeranylation) onto a carboxy terminal cysteine residue of a protein. Rab and Rho proteins are geranylgeranylated, whereas Ras proteins are typically farnesylated. Substrates of FTase and GGTase I share a consensus C-terminal sequence (the \"CAAX\" box) which dictates enzyme recognition. However, GGTase II is unable to recognize Rab proteins directly and instead utilizes the Rab escort protein (REP) which delivers Rab to the enzyme's active site and allows prenylation to occur [1].  
The Ras family of proteins, including H-, K-, and N-Ras, play critical roles in regulating cellular proliferation in normal and cancer cells. The Rho family of proteins is primarily involved in cytoskeletal reorganization, but also plays a role in the survival of malignant cells. Rab proteins regulate nearly  
Figure 1: The mammalian isoprenoid biosynthetic pathway with associated inhibitors.  
Figure 2: Chemical structures of select geranylgeranyl diphosphate synthase (GGDPS) inhibitors.  
all aspects of intracellular membrane trafficking processes, including facilitating vesicle budding, motility, docking, and fusion. Prenylation of the Ras superfamily members, including the Rab proteins, is essential to ensure proper cellular localization and function. For example, mutant Rab proteins, that cannot be geranylgeranylated, are mislocalized and nonfunctional [2]. Given the diverse roles of prenylated proteins in cellular functions, there has been extensive interest in the development of agents which disrupt protein prenylation by inhibiting the IBP. In this review, we discuss IBP inhibitors with particular focus on GGDPS inhibitor development.