4L8M

Human p38 MAP kinase in complex with a Dibenzoxepinone

Summary for 4L8M

• Entry DOI: 10.2210/pdb4l8m/pdb
• Related: 3QUD 3QUE
• Descriptor: Mitogen-activated protein kinase 14, octyl beta-D-glucopyranoside, N-[2-fluoro-5-({9-[2-(morpholin-4-yl)ethoxy]-11-oxo-6,11-dihydrodibenzo[b,e]oxepin-3-yl}amino)phenyl]benzamide, ... (4 entities in total)
• Functional Keywords: protein kinase, selective p38 inhibitor, sar, dibenzoxepinone derivative, dibenzoxepinone, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 42421.40

Authors

Richters, A.,Mayer-Wrangowski, S.C.,Gruetter, C.,Rauh, D. (deposition date: 2013-06-17, release date: 2013-10-30, Last modification date: 2023-09-20)

Primary citation

Baur, B.,Storch, K.,Martz, K.E.,Goettert, M.I.,Richters, A.,Rauh, D.,Laufer, S.A.
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, 2013

PubMed Abstract: 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.

PubMed: 24131218
DOI: 10.1021/jm401276h

Experimental method

X-RAY DIFFRACTION (2.1 Å)