Recent Advances in the Development of Mammalian Geranylgeranyl Diphosphate Synthase Inhibitors

Abstract

The enzyme geranylgeranyl diphosphate synthase (GGDPS) catalyzes the synthesis of the 20-carbon isoprenoid geranylgeranyl diphosphate (GGPP). GGPP is the isoprenoid donor for protein geranylgeranylation reactions catalyzed by the enzymes geranylgeranyl transferase (GGTase) I and II. Inhibitors of GGDPS result in diminution of protein geranylgeranylation through depletion of cellular GGPP levels, and there has been interest in GGDPS inhibitors as potential anti-cancer agents. Here we discuss recent advances in the development of GGDPS inhibitors, including insights gained by structure-function relationships, and review the preclinical data that support the continued development of this novel class of drugs.

Metal Coordination Is Crucial for Geranylgeranyl Diphosphate Synthase–Bisphosphonate Interactions: A Crystallographic and Computational Analysis

“…Their main disadvantages relate to their pharmacokinetics, with limited distribution focused mainly to the bone matrix (Lin, 1996). In addition, some bisphosphonates lack specificity toward GGPPS (Guo et al, 2007), and most of them display poor cell permeability (Haney et al, 2017). Therefore, the design of novel bisphosphonates with improved tissue distribution profiles, such as the lipophilic bisphosphonates (Zhang et al, 2009), bisphosphonates with improved GGPPS specificity (Zhou et al, 2014;Wills et al, 2015Wills et al, , 2017, and nonbisphosphonate GGPPS inhibitors, is highly desired (Merino et al, 2017).…”

“…However, the physicochemical properties of the marketed bisphosphonates render them with poor bioavailability and cell permeability characteristics (Lin, 1996), restricting their therapeutic scope for treatment of bone disorders, in which the drug accumulates locally and permeates the cell membrane via endocytosis during bone resorption (Russell, 2011). Thus, to exploit the full potential of GGPPS inhibition, the design of novel bisphosphonates with modified pharmacokinetic characteristics is required for expansion of their target tissues repertoire (Haney et al, 2017).…”

“…Over the past two decades, several attempts were made to establish robust computational screening approaches to predict the binding potency of bisphosphonates to GGPPS (Szabo et al, 2002;Guo et al, 2007;Haney et al, 2017). These attempts were based on the wealth of structural information obtained using the yeast GGPPS (yGGPPS) ortholog bound to various bisphosphonates (Guo et al, 2007;K-M Chen et al, 2008;Zhang et al, 2009), despite differences in the potency of these drugs toward yGGPPS and hGGPPS (Guo et al, 2007), as the structure of hGGPPS-wild-type (WT) bound to a bisphosphonate was unavailable.…”

Simultaneous Quantitation of Isoprenoid Pyrophosphates in Plasma and Cancer Cells Using LC-MS/MS

“…The isoprenoid biosynthesis pathway (IBP) plays key roles in cellular metabolism and is responsible for the production of both sterol and non-sterol isoprenoids [1,2]. Because the IBP is an important target in many areas of ongoing research, new inhibitors that target specific enzymes in this pathway are under development.…”

“…Clinically utilized IBP inhibitors include the statins, which inhibit HMG CoA reductase and are used to treat hyperlipidemia, and the nitrogenous bisphosphonates, which inhibit farnesyl diphosphate synthase (FDPS) and are used to treat a variety of bone diseases including osteoporosis [3], metastatic bone disease [4] and myeloma bone disease [5]. In addition, there is significant interest in the therapeutic potential of inhibiting this pathway in a variety of other diseases, including cancer [2,6,7,8,9], tuberculosis [1], Parkinson’s disease [10,11,12] and hypercholesteremia [13]. Farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP) are utilized as the isoprenoid donors for protein farnesylation and geranylgeranylation reactions, respectively.…”