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PDBsum entry 2p2h
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References listed in PDB file
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Key reference
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Title
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Evolution of a highly selective and potent 2-(Pyridin-2-Yl)-1,3,5-Triazine tie-2 kinase inhibitor.
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Authors
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B.L.Hodous,
S.D.Geuns-Meyer,
P.E.Hughes,
B.K.Albrecht,
S.Bellon,
J.Bready,
S.Caenepeel,
V.J.Cee,
S.C.Chaffee,
A.Coxon,
M.Emery,
J.Fretland,
P.Gallant,
Y.Gu,
D.Hoffman,
R.E.Johnson,
R.Kendall,
J.L.Kim,
A.M.Long,
M.Morrison,
P.R.Olivieri,
V.F.Patel,
A.Polverino,
P.Rose,
P.Tempest,
L.Wang,
D.A.Whittington,
H.Zhao.
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Ref.
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J Med Chem, 2007,
50,
611-626.
[DOI no: ]
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PubMed id
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Abstract
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Inhibition of angiogenesis is a promising and clinically validated approach for
limiting tumor growth and survival. The receptor tyrosine kinase Tie-2 is
expressed almost exclusively in the vascular endothelium and is required for
developmental angiogenesis and vessel maturation. However, the significance of
Tie-2 signaling in tumor angiogenesis is not well understood. In order to
evaluate the therapeutic utility of inhibiting Tie-2 signaling, we developed a
series of potent and orally bioavailable small molecule Tie-2 kinase inhibitors
with selectivity over other kinases, especially those that are believed to be
important for tumor angiogenesis. Our earlier work provided pyridinyl pyrimidine
6 as a potent, nonselective Tie-2 inhibitor that was designed on the basis of
X-ray cocrystal structures of KDR inhibitors 34 (triazine) and 35
(nicotinamide). Lead optimization resulted in pyridinyl triazine 63, which
exhibited >30-fold selectivity over a panel of kinases, good oral exposure,
and in vivo inhibition of Tie-2 phosphorylation.
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