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We and others have recently shown that the major molecular target of nitrogen-containing bisphosphonate drugs is farnesyl diphosphate synthase, an enzyme in the mevalonate pathway. In an in vitro screen, we discovered a bisphosphonate, NE21650, that potently inhibited farnesyl diphosphate synthase but, unlike other N-BPs investigated, was also a weak inhibitor of isopentenyl diphosphate isomerase. NE21650 was a more potent inhibitor of protein prenylation in osteoclasts and macrophages, and a more potent inhibitor of bone resorption in vitro, than alendronate, despite very similar IC(50) values for inhibition of farnesyl diphosphate synthase. Our observations show that minor changes to the structure of bisphosphonates allow inhibition of more than one enzyme in the mevalonate pathway and suggest that loss of protein prenylation due to inhibition of more than one enzyme in the mevalonate pathway may lead to an increase in antiresorptive potency compared to bisphosphonates that only inhibit farnesyl diphosphate synthase.

Original publication

DOI

10.1006/bbrc.2001.6289

Type

Journal article

Journal

Biochem Biophys Res Commun

Publication Date

18/01/2002

Volume

290

Pages

869 - 873

Keywords

Alendronate, Alkyl and Aryl Transferases, Aniline Compounds, Animals, Carbon-Carbon Double Bond Isomerases, Cells, Cultured, Diphosphonates, Dose-Response Relationship, Drug, Drug Evaluation, Preclinical, Electrophoresis, Polyacrylamide Gel, Geranyltranstransferase, Humans, Macrophages, Osteoclasts, Protein Prenylation, Rabbits