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PDBsum entry 3f9n
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References listed in PDB file
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Key reference
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Title
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Development of thioquinazolinones, Allosteric chk1 kinase inhibitors.
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Authors
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A.Converso,
T.Hartingh,
R.M.Garbaccio,
E.Tasber,
K.Rickert,
M.E.Fraley,
Y.Yan,
C.Kreatsoulas,
S.Stirdivant,
B.Drakas,
E.S.Walsh,
K.Hamilton,
C.A.Buser,
X.Mao,
M.T.Abrams,
S.C.Beck,
W.Tao,
R.Lobell,
L.Sepp-Lorenzino,
J.Zugay-Murphy,
V.Sardana,
S.K.Munshi,
S.M.Jezequel-Sur,
P.D.Zuck,
G.D.Hartman.
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Ref.
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Bioorg Med Chem Lett, 2009,
19,
1240-1244.
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PubMed id
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Abstract
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A high throughput screening campaign was designed to identify allosteric
inhibitors of Chk1 kinase by testing compounds at high concentration. Activity
was then observed at K(m) for ATP and at near-physiological concentrations of
ATP. This strategy led to the discovery of a non-ATP competitive
thioquinazolinone series which was optimized for potency and stability. An X-ray
crystal structure for the complex of our best inhibitor bound to Chk1 was
solved, indicating that it binds to an allosteric site approximately 13A from
the ATP binding site. Preliminary data is presented for several of these
compounds.
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