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PDBsum entry 2ywp
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References listed in PDB file
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Key reference
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Title
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Synthesis and biological evaluation of 1-(2,4,5-Trisubstituted phenyl)-3-(5-Cyanopyrazin-2-Yl)ureas as potent chk1 kinase inhibitors.
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Authors
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G.Li,
L.A.Hasvold,
Z.F.Tao,
G.T.Wang,
S.L.Gwaltney,
J.Patel,
P.Kovar,
R.B.Credo,
Z.Chen,
H.Zhang,
C.Park,
H.L.Sham,
T.Sowin,
S.H.Rosenberg,
N.H.Lin.
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Ref.
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Bioorg Med Chem Lett, 2006,
16,
2293-2298.
[DOI no: ]
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PubMed id
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Abstract
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Based on the X-ray crystallography of our lead compound
1-(5-chloro-2,4-dimethoxyphenyl)-3-(5-cyanopyrazin-2-yl)urea in the checkpoint
kinase 1 (Chk1) enzyme, we modified R4, and to a lesser extent, R2, and R5 of
the phenyl ring, and made a variety of N-aryl-N'-pyrazinylurea Chk1 inhibitors.
Enzymatic activity less than 20 nM was observed in 15 of 41 compounds. Compound
8i provided the best overall results in the cellular assays as it abrogated
doxorubicin-induced cell cycle arrest (IC50=1.7 microM) and enhanced doxorubicin
cytotoxicity (IC50=0.44 microM) while displaying no single agent activity.
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