Potent Triazole Bisphosphonate Inhibitor of Geranylgeranyl Diphosphate Synthase

Abstract

Studies of triazole bisphosphonates have resulted in identification of a potent inhibitor of geranylgeranyl diphosphate synthase (IC50 = 45 nM) with very good selectivity for this enzyme over farnesyl diphosphate synthase (IC50 = 28 μM). This compound also potently disrupts geranylgeranylation and induces cytotoxicity in human myeloma cells at submicromolar levels, suggesting that it may serve as a lead compound for treatment of malignancies characterized by excessive protein secretion.

Keywords: GGDPS; Geranylgeranyl diphosphate synthase; bisphosphonate; farnesyl diphosphate synthase; myeloma.

Figure 1

Bisphosphonates that inhibit isoprenoid biosynthesis.

Scheme 1. Synthesis of Triazole 8 as a ∼3:1 Mixture of E- and Z-Olefin Isomers

Scheme 2. Synthesis of a Dialkyl Bisphosphonate

Figure 2

Effects of novel triazole bisphosphonates in myeloma cells. RPMI-8226 cells were incubated for 48 h in the presence or absence of the triazole bisphosphonates 8, 18, or 20. Cells were also incubated with lovastatin (Lov, 10 μM) as a positive control. (A) Cells were lysed using RIPA buffer to generate whole cell lysate. The Rap1a antibody detects only unmodified protein. β-Tubulin was used as a loading control. The gels are representative of two independent studies. (B) Intracellular lambda light chain concentrations were determined via ELISA. Data are expressed as percentage of control (mean ± SD, n = 3). The * denotes p < 0.05 per unpaired two-tailed t-test and compares treated cells to untreated control cells.