In vivo evaluation of isoprenoid triazole bisphosphonate inhibitors of geranylgeranyl diphosphate synthase: Impact of olefin stereochemistry on toxicity and biodistribution

Staci L. Haney, Yashpal S. Chhonker, Michelle L. Varney, Geoffrey Talmon, Lynette M. Smith, Daryl J. Murry, Sarah A. Holstein

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Abstract

The enzyme geranylgeranyl diphosphate synthase (GGDPS) synthesizes the 20-carbon isoprenoid geranylgeranyl pyrophosphate, which is used in geranylgeranylation reactions. We have demonstrated that GGDPS inhibitors in multiple myeloma (MM) cells disrupt Rab geranylgeranylation, leading to inhibition of monoclonal protein trafficking, induction of the unfolded protein response pathway (UPR), and apoptosis. We have previously reported preclinical studies with the GGDPS inhibitor VSW1198, which is a mixture of homogeranyl/homoneryl triazole bisphosphonates. Additional structure-function efforts have led to development of the a-methylated derivatives RAM2093 (homogeranyl) and RAM2061 (homoneryl). As little is known regarding the impact of olefin stereochemistry on drug properties in vivo, we pursued additional preclinical evaluation of RAM2093 and RAM2061. In MM cell lines, both isomers induce activation of UPR/apoptotic markers in a concentration-dependent manner and with similar potency. Single-dose testing in CD-1 mice identified a maximum tolerated i.v. dose of 0.5 mg/kg for RAM2061 and 0.3 mg/kg for RAM2093. Liver toxicity was the primary barrier to dose escalation for both compounds. Disruption of geranylgeranylation in vivo was confirmed after multidose administration of either compound. Pharmacokinetic studies revealed plasma terminal half-lives of 29.2 6 6 (RAM2061) and 22.1 6 4 hours (RAM2093). Relative to RAM2061, RAM2093 levels were significantly higher in liver tissue but not in other tissues. Using MM.1S flank xenografts, we observed a significant reduction in tumor growth in mice treated with RAM2061 relative to controls. Collectively, these studies reveal olefin stereochemistry-dependent effects on GGDPS inhibitor biodistribution and confirm the in vivo efficacy of this novel therapeutic approach. SIGNIFICANCE STATEMENT These studies reveal olefin stereochemistry-dependent effects on the in vivo properties of two novel triazole bisphosphonate inhibitors of geranylgeranyl diphosphate synthase and demonstrate the therapeutic potential of this class of inhibitors for the treatment of multiple myeloma.

Original languageEnglish (US)
Pages (from-to)327-338
Number of pages12
JournalJournal of Pharmacology and Experimental Therapeutics
Volume371
Issue number2
DOIs
StatePublished - Jan 1 2019

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Farnesyltranstransferase
Triazoles
Terpenes
Diphosphonates
Alkenes
Prenylation
Multiple Myeloma
Unfolded Protein Response
Maximum Tolerated Dose
Liver
Protein Transport
Heterografts
Carbon
Pharmacokinetics
Apoptosis
Cell Line
Enzymes
Therapeutics
Growth
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Cite this

@article{4f22fc630cdd41228bf67e51cc07c8e7,
title = "In vivo evaluation of isoprenoid triazole bisphosphonate inhibitors of geranylgeranyl diphosphate synthase: Impact of olefin stereochemistry on toxicity and biodistribution",
abstract = "The enzyme geranylgeranyl diphosphate synthase (GGDPS) synthesizes the 20-carbon isoprenoid geranylgeranyl pyrophosphate, which is used in geranylgeranylation reactions. We have demonstrated that GGDPS inhibitors in multiple myeloma (MM) cells disrupt Rab geranylgeranylation, leading to inhibition of monoclonal protein trafficking, induction of the unfolded protein response pathway (UPR), and apoptosis. We have previously reported preclinical studies with the GGDPS inhibitor VSW1198, which is a mixture of homogeranyl/homoneryl triazole bisphosphonates. Additional structure-function efforts have led to development of the a-methylated derivatives RAM2093 (homogeranyl) and RAM2061 (homoneryl). As little is known regarding the impact of olefin stereochemistry on drug properties in vivo, we pursued additional preclinical evaluation of RAM2093 and RAM2061. In MM cell lines, both isomers induce activation of UPR/apoptotic markers in a concentration-dependent manner and with similar potency. Single-dose testing in CD-1 mice identified a maximum tolerated i.v. dose of 0.5 mg/kg for RAM2061 and 0.3 mg/kg for RAM2093. Liver toxicity was the primary barrier to dose escalation for both compounds. Disruption of geranylgeranylation in vivo was confirmed after multidose administration of either compound. Pharmacokinetic studies revealed plasma terminal half-lives of 29.2 6 6 (RAM2061) and 22.1 6 4 hours (RAM2093). Relative to RAM2061, RAM2093 levels were significantly higher in liver tissue but not in other tissues. Using MM.1S flank xenografts, we observed a significant reduction in tumor growth in mice treated with RAM2061 relative to controls. Collectively, these studies reveal olefin stereochemistry-dependent effects on GGDPS inhibitor biodistribution and confirm the in vivo efficacy of this novel therapeutic approach. SIGNIFICANCE STATEMENT These studies reveal olefin stereochemistry-dependent effects on the in vivo properties of two novel triazole bisphosphonate inhibitors of geranylgeranyl diphosphate synthase and demonstrate the therapeutic potential of this class of inhibitors for the treatment of multiple myeloma.",
author = "Haney, {Staci L.} and Chhonker, {Yashpal S.} and Varney, {Michelle L.} and Geoffrey Talmon and Smith, {Lynette M.} and Murry, {Daryl J.} and Holstein, {Sarah A.}",
year = "2019",
month = "1",
day = "1",
doi = "10.1124/jpet.119.258624",
language = "English (US)",
volume = "371",
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journal = "Journal of Pharmacology and Experimental Therapeutics",
issn = "0022-3565",
publisher = "American Society for Pharmacology and Experimental Therapeutics",
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TY - JOUR

T1 - In vivo evaluation of isoprenoid triazole bisphosphonate inhibitors of geranylgeranyl diphosphate synthase

T2 - Impact of olefin stereochemistry on toxicity and biodistribution

AU - Haney, Staci L.

AU - Chhonker, Yashpal S.

AU - Varney, Michelle L.

AU - Talmon, Geoffrey

AU - Smith, Lynette M.

AU - Murry, Daryl J.

AU - Holstein, Sarah A.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - The enzyme geranylgeranyl diphosphate synthase (GGDPS) synthesizes the 20-carbon isoprenoid geranylgeranyl pyrophosphate, which is used in geranylgeranylation reactions. We have demonstrated that GGDPS inhibitors in multiple myeloma (MM) cells disrupt Rab geranylgeranylation, leading to inhibition of monoclonal protein trafficking, induction of the unfolded protein response pathway (UPR), and apoptosis. We have previously reported preclinical studies with the GGDPS inhibitor VSW1198, which is a mixture of homogeranyl/homoneryl triazole bisphosphonates. Additional structure-function efforts have led to development of the a-methylated derivatives RAM2093 (homogeranyl) and RAM2061 (homoneryl). As little is known regarding the impact of olefin stereochemistry on drug properties in vivo, we pursued additional preclinical evaluation of RAM2093 and RAM2061. In MM cell lines, both isomers induce activation of UPR/apoptotic markers in a concentration-dependent manner and with similar potency. Single-dose testing in CD-1 mice identified a maximum tolerated i.v. dose of 0.5 mg/kg for RAM2061 and 0.3 mg/kg for RAM2093. Liver toxicity was the primary barrier to dose escalation for both compounds. Disruption of geranylgeranylation in vivo was confirmed after multidose administration of either compound. Pharmacokinetic studies revealed plasma terminal half-lives of 29.2 6 6 (RAM2061) and 22.1 6 4 hours (RAM2093). Relative to RAM2061, RAM2093 levels were significantly higher in liver tissue but not in other tissues. Using MM.1S flank xenografts, we observed a significant reduction in tumor growth in mice treated with RAM2061 relative to controls. Collectively, these studies reveal olefin stereochemistry-dependent effects on GGDPS inhibitor biodistribution and confirm the in vivo efficacy of this novel therapeutic approach. SIGNIFICANCE STATEMENT These studies reveal olefin stereochemistry-dependent effects on the in vivo properties of two novel triazole bisphosphonate inhibitors of geranylgeranyl diphosphate synthase and demonstrate the therapeutic potential of this class of inhibitors for the treatment of multiple myeloma.

AB - The enzyme geranylgeranyl diphosphate synthase (GGDPS) synthesizes the 20-carbon isoprenoid geranylgeranyl pyrophosphate, which is used in geranylgeranylation reactions. We have demonstrated that GGDPS inhibitors in multiple myeloma (MM) cells disrupt Rab geranylgeranylation, leading to inhibition of monoclonal protein trafficking, induction of the unfolded protein response pathway (UPR), and apoptosis. We have previously reported preclinical studies with the GGDPS inhibitor VSW1198, which is a mixture of homogeranyl/homoneryl triazole bisphosphonates. Additional structure-function efforts have led to development of the a-methylated derivatives RAM2093 (homogeranyl) and RAM2061 (homoneryl). As little is known regarding the impact of olefin stereochemistry on drug properties in vivo, we pursued additional preclinical evaluation of RAM2093 and RAM2061. In MM cell lines, both isomers induce activation of UPR/apoptotic markers in a concentration-dependent manner and with similar potency. Single-dose testing in CD-1 mice identified a maximum tolerated i.v. dose of 0.5 mg/kg for RAM2061 and 0.3 mg/kg for RAM2093. Liver toxicity was the primary barrier to dose escalation for both compounds. Disruption of geranylgeranylation in vivo was confirmed after multidose administration of either compound. Pharmacokinetic studies revealed plasma terminal half-lives of 29.2 6 6 (RAM2061) and 22.1 6 4 hours (RAM2093). Relative to RAM2061, RAM2093 levels were significantly higher in liver tissue but not in other tissues. Using MM.1S flank xenografts, we observed a significant reduction in tumor growth in mice treated with RAM2061 relative to controls. Collectively, these studies reveal olefin stereochemistry-dependent effects on GGDPS inhibitor biodistribution and confirm the in vivo efficacy of this novel therapeutic approach. SIGNIFICANCE STATEMENT These studies reveal olefin stereochemistry-dependent effects on the in vivo properties of two novel triazole bisphosphonate inhibitors of geranylgeranyl diphosphate synthase and demonstrate the therapeutic potential of this class of inhibitors for the treatment of multiple myeloma.

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