title: Design and synthesis of active site inhibitors of the human farnesyl pyrophosphate synthase: apoptosis and inhibition of ERK phosphorylation in multiple myeloma cells.
abstract: Human farnesyl pyrophosphate synthase (hFPPS) controls intracellular levels of FPP and post-translational prenylation of small GTPase proteins, which are essential for cell signaling and cell proliferation. Clinical investigations provide evidence that N-BP inhibitors of hFPPS are disease modifying agents that improve survival of multiple myeloma (MM) patients via mechanisms unrelated to their skeletal effects. A new series of N-BPs was designed that interact with a larger portion of the GPP subpocket, as compared to the current therapeutic drugs, and rigidify the (364)KRRK(367) tail of hFPPS in the closed conformation in the absence of IPP. An analogue of this series was used to demonstrate inhibition of the intended biological target, resulting in apoptosis and down-regulation of ERK phosphorylation in human MM cell lines.
authors.affiliation: Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montreal, QC, Canada H3A 0B8.
authors.forename: Yih-Shyan
authors.initials: YS
authors.lastname: Lin
authors.forename: Jaeok
authors.initials: J
authors.lastname: Park
authors.forename: Joris W
authors.initials: JW
authors.lastname: De Schutter
authors.forename: Xian Fang
authors.initials: XF
authors.lastname: Huang
authors.forename: Albert M
authors.initials: AM
authors.lastname: Berghuis
authors.forename: Michael
authors.initials: M
authors.lastname: Sebag
authors.forename: Youla S
authors.initials: YS
authors.lastname: Tsantrizos
mesh_terms: D000631:Aminopyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000814:Aniline Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D020134:Catalytic Domain; D002470:Cell Survival / Q000187:drug effects; D018360:Crystallography, X-Ray; D004164:Diphosphonates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D051228:Geranyltranstransferase / Q000037:antagonists & inhibitors*; D045782:Hemiterpenes / Q000737:chemistry; D006801:Humans; D008958:Models, Molecular; D009101:Multiple Myeloma / Q000378:metabolism / Q000473:pathology*; D009943:Organophosphorus Compounds / Q000737:chemistry; D010766:Phosphorylation; D011487:Protein Conformation; D054852:Small Molecule Libraries; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000631:Aminopyridines; D000814:Aniline Compounds; D000970:Antineoplastic Agents; D004164:Diphosphonates; D045782:Hemiterpenes; D009943:Organophosphorus Compounds; D054852:Small Molecule Libraries; C004809:isopentenyl pyrophosphate; D051228:Geranyltranstransferase; D048049:Extracellular Signal-Regulated MAP Kinases