title: Lipophilic bisphosphonates as dual farnesyl/geranylgeranyl diphosphate synthase inhibitors: an X-ray and NMR investigation.
abstract: Considerable effort has focused on the development of selective protein farnesyl transferase (FTase) and protein geranylgeranyl transferase (GGTase) inhibitors as cancer chemotherapeutics. Here, we report a new strategy for anticancer therapeutic agents involving inhibition of farnesyl diphosphate synthase (FPPS) and geranylgeranyl diphosphate synthase (GGPPS), the two enzymes upstream of FTase and GGTase, by lipophilic bisphosphonates. Due to dual site targeting and decreased polarity, the compounds have activities far greater than do current bisphosphonate drugs in inhibiting tumor cell growth and invasiveness, both in vitro and in vivo. We explore how these compounds inhibit cell growth and how cell activity can be predicted based on enzyme inhibition data, and using X-ray diffraction, solid state NMR, and isothermal titration calorimetry, we show how these compounds bind to FPPS and/or GGPPS.
authors.affiliation: Department of Chemistry, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue, Urbana, Illinois 61801, USA.
authors.forename: Yonghui
authors.initials: Y
authors.lastname: Zhang
authors.forename: Rong
authors.initials: R
authors.lastname: Cao
authors.forename: Fenglin
authors.initials: F
authors.lastname: Yin
authors.forename: Michael P
authors.initials: MP
authors.lastname: Hudock
authors.forename: Rey-Ting
authors.initials: RT
authors.lastname: Guo
authors.forename: Kilannin
authors.initials: K
authors.lastname: Krysiak
authors.forename: Sujoy
authors.initials: S
authors.lastname: Mukherjee
authors.forename: Yi-Gui
authors.initials: YG
authors.lastname: Gao
authors.forename: Howard
authors.initials: H
authors.lastname: Robinson
authors.forename: Yongcheng
authors.initials: Y
authors.lastname: Song
authors.forename: Joo Hwan
authors.initials: JH
authors.lastname: No
authors.forename: Kyle
authors.initials: K
authors.lastname: Bergan
authors.forename: Annette
authors.initials: A
authors.lastname: Leon
authors.forename: Lauren
authors.initials: L
authors.lastname: Cass
authors.forename: Amanda
authors.initials: A
authors.lastname: Goddard
authors.forename: Ting-Kai
authors.initials: TK
authors.lastname: Chang
authors.forename: Fu-Yang
authors.initials: FY
authors.lastname: Lin
authors.forename: Ermond
authors.initials: E
authors.lastname: Van Beek
authors.forename: Socrates
authors.initials: S
authors.lastname: Papapoulos
authors.forename: Andrew H-J
authors.initials: AH
authors.lastname: Wang
authors.forename: Tadahiko
authors.initials: T
authors.lastname: Kubo
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Ochi
authors.forename: Dushyant
authors.initials: D
authors.lastname: Mukkamala
authors.forename: Eric
authors.initials: E
authors.lastname: Oldfield
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D004164:Diphosphonates / Q000737:chemistry* / Q000494:pharmacology*; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D051228:Geranyltranstransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D006801:Humans; D008055:Lipids / Q000737:chemistry; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D019906:Nuclear Magnetic Resonance, Biomolecular; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000201:enzymology; D029701:Saccharomyces cerevisiae Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D014346:Trypanosoma brucei brucei / Q000201:enzymology
chemical_list: D004164:Diphosphonates; D008055:Lipids; D015800:Protozoan Proteins; D029701:Saccharomyces cerevisiae Proteins; D051228:Geranyltranstransferase; D051231:Farnesyltranstransferase