Identification of a bisphosphonate that inhibits isopentenyl diphosphate isomerase and farnesyl diphosphate synthase.
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.
Thompson
Keith
K
Bone Research Group, Department of Medicine & Therapeutics, Proctor & Gamble Pharmaceuticals, Health Care Research Center, Mason, Scotland, 45040, United Kingdom.
Dunford
James E
JE
Ebetino
Frank H
FH
Rogers
Michael J
MJ
D019386:Alendronate / Q000494:pharmacology; D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000814:Aniline Compounds / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D019748:Carbon-Carbon Double Bond Isomerases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002478:Cells, Cultured; D004164:Diphosphonates / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004591:Electrophoresis, Polyacrylamide Gel; D051228:Geranyltranstransferase; D045782:Hemiterpenes; D006801:Humans; D008264:Macrophages / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D017368:Protein Prenylation / Q000187:drug effects; D011817:Rabbits
D000814:Aniline Compounds; D004164:Diphosphonates; D045782:Hemiterpenes; C446302:NE 21650; D019883:Alkyl and Aryl Transferases; D051228:Geranyltranstransferase; D019748:Carbon-Carbon Double Bond Isomerases; C021453:isopentenyldiphosphate delta-isomerase; D019386:Alendronate