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PDBsum entry 4l8m
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Transferase/transferase inhibitor
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PDB id
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4l8m
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PDB id:
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| Name: |
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Transferase/transferase inhibitor
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Title:
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Human p38 map kinase in complex with a dibenzoxepinone
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Structure:
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Mitogen-activated protein kinase 14. Chain: a. Fragment: p38 map kinase. Synonym: map kinase 14, mapk 14, cytokine suppressive anti- inflammatory drug-binding protein, csaid-binding protein, csbp, map kinase mxi2, max-interacting protein 2, mitogen-activated protein kinase p38 alpha, map kinase p38 alpha, stress-activated protein kinase 2a, sapk2a. Engineered: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: mapk14, csbp, csbp1, csbp2, cspb1, mxi2, sapk2a. Expressed in: escherichia coli. Expression_system_taxid: 469008.
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Resolution:
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2.10Å
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R-factor:
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0.223
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R-free:
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0.279
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Authors:
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A.Richters,S.C.Mayer-Wrangowski,C.Gruetter,D.Rauh
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Key ref:
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B.Baur
et al.
(2013).
Metabolically stable dibenzo[b,e]oxepin-11(6H)-ones as highly selective p38 MAP kinase inhibitors: optimizing anti-cytokine activity in human whole blood.
J Med Chem,
56,
8561-8578.
PubMed id:
DOI:
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Date:
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17-Jun-13
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Release date:
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30-Oct-13
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PROCHECK
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Headers
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References
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Q16539
(MK14_HUMAN) -
Mitogen-activated protein kinase 14 from Homo sapiens
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Seq:
Struc:
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360 a.a.
339 a.a.
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Key: |
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PfamA domain |
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Secondary structure |
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CATH domain |
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Enzyme class:
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E.C.2.7.11.24
- mitogen-activated protein kinase.
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Reaction:
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1.
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L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H+
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2.
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L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H+
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L-seryl-[protein]
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+
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ATP
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=
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O-phospho-L-seryl-[protein]
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+
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ADP
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+
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H(+)
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L-threonyl-[protein]
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+
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ATP
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=
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O-phospho-L-threonyl-[protein]
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+
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ADP
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+
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H(+)
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Molecule diagrams generated from .mol files obtained from the
KEGG ftp site
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DOI no:
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J Med Chem
56:8561-8578
(2013)
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PubMed id:
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Metabolically stable dibenzo[b,e]oxepin-11(6H)-ones as highly selective p38 MAP kinase inhibitors: optimizing anti-cytokine activity in human whole blood.
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B.Baur,
K.Storch,
K.E.Martz,
M.I.Goettert,
A.Richters,
D.Rauh,
S.A.Laufer.
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ABSTRACT
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Five series of metabolically stable disubstituted dibenzo[b,e]oxepin-11(6H)-ones
were synthesized and tested in a p38α enzyme assay for their inhibition of
tumor necrosis factor-α (TNF-α) release in human whole blood. Compared to the
monosubstituted dibenzo[b,e]oxepin-11(6H)-one derivatives, it has been shown
that the additional introduction of hydrophilic residues at position 9 leads to
a substantial improvement of the inhibitory potency and metabolic stability.
Using protein X-ray crystallography, the binding mode of the disubstituted
dibenzoxepinones and the induction of a glyince flip in the hinge region were
confirmed. The most potent compound of this series, 32e, shows an outstanding
biological activity on isolated p38α, with an IC50 value of 1.6 nM,
extraordinary selectivity (by a factor >1000, Kinase WholePanelProfiler), and
low ATP competitiveness. The ability to inhibit the release of TNF-α from human
whole blood was optimized down to an IC50 value of 125 nM. With the promising
dibenzoxepinone inhibitor 3i, a pharmacokinetic study in mice was conducted.
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Links
