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PDBsum entry 3dyh
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References listed in PDB file
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Key reference
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Title
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Lipophilic bisphosphonates as dual farnesyl/geranylgeranyl diphosphate synthase inhibitors: an X-Ray and nmr investigation.
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Authors
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Y.Zhang,
R.Cao,
F.Yin,
M.P.Hudock,
R.T.Guo,
K.Krysiak,
S.Mukherjee,
Y.G.Gao,
H.Robinson,
Y.Song,
J.H.No,
K.Bergan,
A.Leon,
L.Cass,
A.Goddard,
T.K.Chang,
F.Y.Lin,
E.Van beek,
S.Papapoulos,
A.H.Wang,
T.Kubo,
M.Ochi,
D.Mukkamala,
E.Oldfield.
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Ref.
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J Am Chem Soc, 2009,
131,
5153-5162.
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PubMed id
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Abstract
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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.
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