Premium
Identification and characterization of novel bisphosphonate inhibitors of squalene synthase
Author(s) -
Wasko Brian M.,
Smits Jacqueline P.,
Tong Huaxiang,
Wiemer David F.,
Hohl Raymond J.
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.681.15
Subject(s) - squalene , prenylation , lovastatin , farnesyl diphosphate synthase , farnesyl diphosphate farnesyltransferase , biochemistry , mevalonic acid , atp synthase , enzyme , chemistry , mevalonate pathway , farnesyl pyrophosphate , fluvastatin , pharmacology , biosynthesis , biology , farnesyltransferase , cholesterol , simvastatin
At the branch point of the isoprenoid biosynthetic pathway, squalene synthase (SQS) is an enzyme that utilizes farnesyl diphosphate (FPP) to make squalene, which is first committed step in the biosynthesis of cholesterol. A recombinant form of human SQS has been purified and in vitro assays have been established to measure enzyme activity. We have evaluated structure activity relationships among more than 30 novel bisphosphonates and have identified 9‐biphenyl geranyl bisphosphonate (BPGB) as a potent inhibitor of SQS (IC 50 = 10 nM). Western blot analysis of farnesylated and geranylgeranylated proteins from HepG2 cells indicates that treatment with BGBP is specific for the sterol branch of the pathway and not other isoprenoid enzymes (i.e., farnesyl diphosphate synthase or geranylgeranyl diphosphate synthase). The coadministration of lovastatin with BGBP can prevent lovastatin‐induced inhibition of protein prenylation. BGBP at 25 μM for 24 hours resulted in more than 20 fold accumulation of the substrate FPP. In conclusion, this data identifies a novel and specific inhibitor of SQS and evaluates some of the cellular effects of squalene synthase inhibition. Research support comes from the Roy J. Carver Charitable Trust and the Roland W. Holden Family Program for Experimental Cancer Therapeutics.