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PDBsum entry 2hxl
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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 6-Substituted indolylquinolinones as potent chek1 kinase inhibitors.
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Authors
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S.Huang,
R.M.Garbaccio,
M.E.Fraley,
J.Steen,
C.Kreatsoulas,
G.Hartman,
S.Stirdivant,
B.Drakas,
K.Rickert,
E.Walsh,
K.Hamilton,
C.A.Buser,
J.Hardwick,
X.Mao,
M.Abrams,
S.Beck,
W.Tao,
R.Lobell,
L.Sepp-Lorenzino,
Y.Yan,
M.Ikuta,
J.Z.Murphy,
V.Sardana,
S.Munshi,
L.Kuo,
M.Reilly,
E.Mahan.
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Ref.
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Bioorg Med Chem Lett, 2006,
16,
5907-5912.
[DOI no: ]
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PubMed id
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Abstract
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Through a comparison of X-ray co-crystallographic data for 1 and 2 in the Chek1
active site, it was hypothesized that the affinity of the indolylquinolinone
series (2) for Chek1 kinase would be improved via C6 substitution into the
hydrophobic region I (HI) pocket. An efficient route to
6-bromo-3-indolyl-quinolinone (9) was developed, and this series was rapidly
optimized for potency by modification at C6. A general trend was observed among
these low nanomolar Chek1 inhibitors that compounds with multiple basic amines,
or elevated polar surface area (PSA) exhibited poor cell potency. Minimization
of these parameters (basic amines, PSA) resulted in Chek1 inhibitors with
improved cell potency, and preliminary pharmacokinetic data are presented for
several of these compounds.
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