Lipophilic bisphosphonates as dual farnesyl/geranylgeranyl diphosphate synthase inhibitors: an X-ray and NMR investigation.
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.
Zhang
Yonghui
Y
Department of Chemistry, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue, Urbana, Illinois 61801, USA.
Cao
Rong
R
Yin
Fenglin
F
Hudock
Michael P
MP
Guo
Rey-Ting
RT
Krysiak
Kilannin
K
Mukherjee
Sujoy
S
Gao
Yi-Gui
YG
Robinson
Howard
H
Song
Yongcheng
Y
No
Joo Hwan
JH
Bergan
Kyle
K
Leon
Annette
A
Cass
Lauren
L
Goddard
Amanda
A
Chang
Ting-Kai
TK
Lin
Fu-Yang
FY
Van Beek
Ermond
E
Papapoulos
Socrates
S
Wang
Andrew H-J
AH
Kubo
Tadahiko
T
Ochi
Mitsuo
M
Mukkamala
Dushyant
D
Oldfield
Eric
E
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
D004164:Diphosphonates; D008055:Lipids; D015800:Protozoan Proteins; D029701:Saccharomyces cerevisiae Proteins; D051228:Geranyltranstransferase; D051231:Farnesyltranstransferase