 |
PDBsum entry 3ce3
|
|
|
|
References listed in PDB file
|
 |
|
Key reference
|
|
|
Title
|
|
Discovery of pyrrolopyridine-Pyridone based inhibitors of met kinase: synthesis, X-Ray crystallographic analysis, And biological activities.
|
|
|
Authors
|
|
K.S.Kim,
L.Zhang,
R.Schmidt,
Z.W.Cai,
D.Wei,
D.K.Williams,
L.J.Lombardo,
G.L.Trainor,
D.Xie,
Y.Zhang,
Y.An,
J.S.Sack,
J.S.Tokarski,
C.Darienzo,
A.Kamath,
P.Marathe,
Y.Zhang,
J.Lippy,
R.Jeyaseelan,
B.Wautlet,
B.Henley,
J.Gullo-Brown,
V.Manne,
J.T.Hunt,
J.Fargnoli,
R.M.Borzilleri.
|
|
|
Ref.
|
|
J Med Chem, 2008,
51,
5330-5341.
|
|
|
PubMed id
|
|
|
|
|
|
Abstract
|
|
|
Conformationally constrained 2-pyridone analogue 2 is a potent Met kinase
inhibitor with an IC50 value of 1.8 nM. Further SAR of the 2-pyridone based
inhibitors of Met kinase led to potent 4-pyridone and pyridine N-oxide
inhibitors such as 3 and 4. The X-ray crystallographic data of the inhibitor 2
bound to the ATP binding site of Met kinase protein provided insight into the
binding modes of these inhibitors, and the SAR of this series of analogues was
rationalized. Many of these analogues showed potent antiproliferative activities
against the Met dependent GTL-16 gastric carcinoma cell line. Compound 2 also
inhibited Flt-3 and VEGFR-2 kinases with IC50 values of 4 and 27 nM,
respectively. It possesses a favorable pharmacokinetic profile in mice and
demonstrates significant in vivo antitumor activity in the GTL-16 human gastric
carcinoma xenograft model.
|
|
|
|
|
|
|
