5MTX

Dibenzooxepinone inhibitor 12b in complex with p38 MAPK

5MTX の概要

• エントリーDOI: 10.2210/pdb5mtx/pdb
• 分子名称: Mitogen-activated protein kinase 14, 3-[(3-benzamido-4-fluoranyl-phenyl)amino]-~{N}-(2-morpholin-4-ylethyl)-11-oxidanylidene-6~{H}-benzo[c][1]benzoxepine-9-carboxamide, octyl beta-D-glucopyranoside, ... (4 entities in total)
• 機能のキーワード: kinase, inhibitor, p38, complex, type 1.5, transferase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 42522.56

構造登録者

Buehrmann, M.,Rauh, D. (登録日: 2017-01-11, 公開日: 2017-09-06, 最終更新日: 2024-05-08)

主引用文献

Walter, N.M.,Wentsch, H.K.,Buhrmann, M.,Bauer, S.M.,Doring, E.,Mayer-Wrangowski, S.,Sievers-Engler, A.,Willemsen-Seegers, N.,Zaman, G.,Buijsman, R.,Lammerhofer, M.,Rauh, D.,Laufer, S.A.
Design, Synthesis, and Biological Evaluation of Novel Type I(1)/2 p38 alpha MAP Kinase Inhibitors with Excellent Selectivity, High Potency, and Prolonged Target Residence Time by Interfering with the R-Spine.
J. Med. Chem., 60:8027-8054, 2017

PubMed Abstract: We recently reported 1a (skepinone-L) as a type I p38α MAP kinase inhibitor with high potency and excellent selectivity in vitro and in vivo. However, as a type I inhibitor, it is entirely ATP-competitive and shows just a moderate residence time. Thus, the scope was to develop a new class of advanced compounds maintaining the structural binding features of skepinone-L scaffold like inducing a glycine flip at the hinge region and occupying both hydrophobic regions I and II. Extending this scaffold with suitable residues resulted in an interference with the kinase's R-Spine. By synthesizing 69 compounds, we could significantly prolong the target residence time with one example to 3663 s, along with an excellent selectivity score of 0.006 and an outstanding potency of 1.0 nM. This new binding mode was validated by cocrystallization, showing all binding interactions typifying type I/ binding. Moreover, microsomal studies showed convenient metabolic stability of the most potent, herein reported representatives.

PubMed: 28834431
DOI: 10.1021/acs.jmedchem.7b00745

実験手法

X-RAY DIFFRACTION (1.8 Å)