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. 2015 Oct 28;6(12):1195-8.
doi: 10.1021/acsmedchemlett.5b00334. eCollection 2015 Dec 10.

Potent Triazole Bisphosphonate Inhibitor of Geranylgeranyl Diphosphate Synthase

Veronica S Wills  1 , Cheryl Allen  2 , Sarah A Holstein  2 , David F Wiemer  3
Affiliations

Potent Triazole Bisphosphonate Inhibitor of Geranylgeranyl Diphosphate Synthase

Veronica S Wills et al. ACS Med Chem Lett. .

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.

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Conflict of interest statement

The authors declare the following competing financial interest(s): D.F.W. is a named inventor of intellectual property related to digeranyl bisphosphonate that is owned by the University of Iowa Research Foundation. He is a founder of Terpenoid Therapeutics, Inc., which has licensed this property.

Figures

Figure 1
Figure 1
Bisphosphonates that inhibit isoprenoid biosynthesis.
Scheme 1
Scheme 1. Synthesis of Triazole 8 as a ∼3:1 Mixture of E- and Z-Olefin Isomers
Scheme 2
Scheme 2. Synthesis of a Dialkyl Bisphosphonate
Figure 2
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.
See this image and copyright information in PMC

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