Preclinical investigation of a potent geranylgeranyl diphosphate synthase inhibitor

Investigational New Drugs
Staci L HaneySarah A Holstein

Abstract

Geranylgeranyl diphosphate synthase (GGDPS) is the enzyme in the isoprenoid biosynthesis pathway that catalyzes the synthesis of the 20-carbon isoprenoid GGPP, which serves as the isoprenoid donor for protein geranylgeranylation reactions. Rab proteins mediate vesicle trafficking within the cell and their activity is dependent on geranylgeranylation. Our prior work has demonstrated that agents that disrupt Rab geranylgeranylation disrupt monoclonal protein trafficking in myeloma cells, resulting in induction of the unfolded protein response pathway and apoptosis. VSW1198 is a potent GGDPS inhibitor with measurable cellular activity at concentrations as low as 30 nM. Due to its potent activity against myeloma cells in vitro, we were interested in evaluating the toxicology profile, pharmacokinetic (PK) profile, tissue distribution pattern and metabolic stability of VSW1198 in preparation for in vivo efficacy studies. Single dose testing via IV administration in CD-1 mice revealed a maximum tolerated dose of 0.5 mg/kg. Doses ≥1 mg/kg resulted in liver toxicity that peaked around 6-7 days post-injection. Disruption of protein geranylgeranylation following repeat dosing of VSW1198 was confirmed via immunoblot analysis of unmodified ...Continue Reading

References

Jun 13, 2003·Molecular Biology of the Cell·Anita Q GomesMiguel C Seabra
May 7, 2009·Molecular Cancer Therapeutics·Jie LuFuyuhiko Tamanoi
Sep 14, 2010·Bioorganic & Medicinal Chemistry·Rocky J BarneyDavid F Wiemer
Apr 15, 2014·Bioorganic & Medicinal Chemistry·Xiang ZhouSarah A Holstein
May 11, 2015·Free Radical Biology & Medicine·Heather L Osborn-HeafordA Brent Carter
Jun 14, 2015·Clinical & Experimental Metastasis·Jacqueline E ReillyRaymond J Hohl
Dec 30, 2015·ACS Medicinal Chemistry Letters·Veronica S WillsDavid F Wiemer
Aug 19, 2016·Molecular Membrane Biology·Sherry S AgabitiAndrew J Wiemer
Sep 15, 2016·Cancer Biology & Therapy·Jacqueline E ReillyRaymond J Hohl
Sep 21, 2016·The Journal of Organic Chemistry·Robert A MatthiesenDavid F Wiemer
May 31, 2017·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Staci L HaneySarah A Holstein
Feb 20, 2018·Journal of Pharmaceutical and Biomedical Analysis·Yashpal S ChhonkerDaryl J Murry

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Citations

Apr 27, 2019·Expert Opinion on Therapeutic Patents·Sarah A Holstein
Oct 2, 2019·Cell Death & Disease·Sherry S AgabitiAndrew J Wiemer
Feb 19, 2019·Critical Reviews in Biochemistry and Molecular Biology·Daniel D WallerYoula S Tsantrizos
Dec 14, 2018·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Yashpal S ChhonkerDaryl J Murry
Mar 6, 2021·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Staci L HaneySarah A Holstein
Jul 24, 2021·Bioorganic & Medicinal Chemistry·Alisa E R FairweatherSarah A Holstein
Jul 9, 2021·Journal of Medicinal Chemistry·Edyta Gendaszewska-DarmachKatarzyna M Błażewska

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