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PDBsum entry 6ekd
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References listed in PDB file
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Key reference
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Title
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Structural optimization of a pyridinylimidazole scaffold: shifting the selectivity from p38α mitogen-Activated protein kinase to c-Jun n-Terminal kinase 3.
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Authors
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F.Ansideri,
J.T.Macedo,
M.Eitel,
A.El-Gokha,
D.S.Zinad,
C.Scarpellini,
M.Kudolo,
D.Schollmeyer,
F.M.Boeckler,
B.S.Blaum,
S.A.Laufer,
P.Koch.
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Ref.
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ACS Omega, 2018,
3,
7809-7831.
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PubMed id
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Abstract
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Starting from known p38α mitogen-activated protein kinase (MAPK) inhibitors, a
series of inhibitors of the c-Jun N-terminal kinase (JNK) 3 was obtained.
Altering the substitution pattern of the pyridinylimidazole scaffold proved to
be effective in shifting the inhibitory activity from the original target p38α
MAPK to the closely related JNK3. In particular, a significant improvement for
JNK3 selectivity could be achieved by addressing the hydrophobic region I with a
small methyl group. Furthermore, additional structural modifications permitted
to explore structure-activity relationships. The most potent inhibitor
4-(4-methyl-2-(methylthio)-1H-imidazol-5-yl)-N-(4-morpholinophenyl)pyridin-2-amine
showed an IC50 value for the JNK3 in the low triple digit nanomolar
range and its binding mode was confirmed by X-ray crystallography.
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