Targeting the Hinge Glycine Flip and the Activation Loop: Novel Approach to Potent p38伪 Inhibitors
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- 作者：Kathrin E. Martz ; Angelika Dorn ; Benjamin Baur ; Verena Schattel ; M谩rcia I. Goettert ; Svenja C. Mayer-Wrangowski ; Daniel Rauh ; Stefan A. Laufer
- 刊名：Journal of Medicinal Chemistry
- 出版年：2012
- 出版时间：September 13, 2012
- 年：2012
- 卷：55
- 期：17
- 页码：7862-7874
- 全文大小：571K
- 年卷期：v.55,no.17(September 13, 2012)
- ISSN：1520-4804
文摘
The p38 MAP kinase is a key player in signaling pathways regulating the biosynthesis of inflammatory cytokines. Small molecule p38 inhibitors suppress the production of these cytokines. Therefore p38 is a promising drug target for novel anti-inflammatory drugs. In this study, we report novel dibenzepinones, dibenzoxepines, and benzosuberones as p38伪 MAP kinase inhibitors. Previously reported dibenzepinones and dibenzoxepines were chemically modified by introduction of functional groups or removal of a phenyl ring. This should result in targeting of the hydrophobic region I, the 鈥渄eep pocket鈥? and the hinge glycine flip of the kinase. Potent inhibitors with IC50 values in the single digit nanomolar range (up to 3 nM) were identified. Instead of targeting the 鈥渄eep pocket鈥?in the DFG-out conformation, interactions with the DFG-motif in the in-conformation could be observed by protein X-ray crystallography.