title: Thienopyrimidine bisphosphonate (ThPBP) inhibitors of the human farnesyl pyrophosphate synthase: optimization and characterization of the mode of inhibition.
abstract: Human farnesyl pyrophosphate synthase (hFPPS) controls the post-translational prenylation of small GTPase proteins that are essential for cell signaling, cell proliferation, and osteoclast-mediated bone resorption. Inhibition of hFPPS is a clinically validated mechanism for the treatment of lytic bone diseases, including osteoporosis and cancer related bone metastases. A new series of thienopyrimidine-based bisphosphonates (ThP-BPs) were identified that inhibit hFPPS with low nanomolar potency. Crystallographic evidence revealed binding of ThP-BP inhibitors in the allylic subpocket of hFPPS. Simultaneous binding of inorganic pyrophosphate in the IPP subpocket leads to conformational closing of the active site cavity. The ThP-BP analogues are significantly less hydrophilic yet exhibit higher affinity for the bone mineral hydroxyapatite than the current N-BP drug risedronic acid. The antiproliferation properties of a potent ThB-BP analogue was assessed in a multiple myeloma cell line and found to be equipotent to the best current N-BP drugs. Consequently, these compounds represent a new structural class of hFPPS inhibitors and a novel scaffold for the development of human therapeutics.
authors.affiliation: Department of Chemistry, McGill University , 801 Sherbrooke Street West, Montreal, Quebec, Canada H3A 0B8.
authors.forename: Chun Yuen
authors.initials: CY
authors.lastname: Leung
authors.forename: Jaeok
authors.initials: J
authors.lastname: Park
authors.forename: Joris W
authors.initials: JW
authors.lastname: De Schutter
authors.forename: Michael
authors.initials: M
authors.lastname: Sebag
authors.forename: Albert M
authors.initials: AM
authors.lastname: Berghuis
authors.forename: Youla S
authors.initials: YS
authors.lastname: Tsantrizos
mesh_terms: D020134:Catalytic Domain; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D011756:Diphosphates / Q000737:chemistry / Q000378:metabolism; D004164:Diphosphonates / Q000737:chemistry / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D051228:Geranyltranstransferase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D011756:Diphosphates; D004164:Diphosphonates; D004791:Enzyme Inhibitors; D011743:Pyrimidines; C476003:thienopyrimidine; D051228:Geranyltranstransferase