898537-77-4Relevant articles and documents
Biophysical investigation and conformational analysis of p38α kinase inhibitor doramapimod and its analogues
Nasiri, Amir H.,Saxena, Krishna,Bats, Jan W.,Nasiri, Hamid R.,Schwalbe, Harald
, p. 1421 - 1428 (2016/07/21)
Doramapimod (BIRB 796) is a potent inhibitor of p38α mitogen-activated protein kinase. It contains an aryl-pyrazole scaffold as a pharmacophore critical for binding. The aryl-pyrazole scaffold is not planar and adopts an out-of-plane conformation, which is described by the torsion angle θ. In this letter, we report the chemical synthesis and biophysical characterization of different analogues of doramapimod (3-12) exhibiting distinctly different aryl-pyrazole torsion angle θ values. The torsion angle θ values of the synthesized analogues (3-6) were determined by crystal structural analysis and the binding affinities to p38α kinase investigated by microscale thermophoresis. Our results unveil a clear correlation between kinase binding and the torsion angle θ of tested doramapimod analogues, highlighting the importance of inhibitor conformation for protein binding.
Synthesis and Biological Evaluation of Chromenylurea and Chromanylurea Derivatives as Anti-TNF-a agents that Target the p38 MAPK Pathway
Li, Xingzhou,Zhou, Xinming,Zhang, Jing,Wang, Lili,Long, Long,Zheng, Zhibing,Li, Song,Zhong, Wu
, p. 2004 - 2028 (2014/03/21)
A series of 1-aryl-3-(2H-chromen-5-yl)urea and 1-aryl-3-(chroman-5-yl)urea derivatives were designed, synthesized and evaluated for their inhibitory activities towards TNF-a production in lipopolysaccharide-stimulated THP-1 cells. The most active compound, 40g, inhibited TNF-a release with an IC50 value of 0.033 μM, which is equipotent to that of BIRB796 (IC50 = 0.032 μM).
Hybrid compound design to overcome the gatekeeper T338M mutation in cSrc
Getlik, Matth?us,Grütter, Christian,Simard, Jeffrey R.,Klüter, Sabine,Rabiller, Matthias,Rode, Haridas B.,Robubi, Armin,Rauh, Daniel
supporting information; experimental part, p. 3915 - 3926 (2009/12/28)
The emergence of drug resistance remains a fundamental challenge in the development of kinase inhibitors that are effective over long-term treatments. Allosteric inhibitors that bind to sites lying outside the highly conserved ATP pocket are thought to be more selective than ATP-competitive inhibitors and may circumvent some mechanisms of drug resistance. Crystal structures of type I and allosteric type III inhibitors in complex with the tyrosine kinase cSrc allowed us to employ principles of structure-based design to develop these scaffolds into potent type II kinase inhibitors. One of these compounds, 3c (RL46), disrupts FAK-mediated focal adhesions in cancer cells via direct inhibition of cSrc. Details gleaned from crystal structures revealed a key feature of a subset of these compounds, a surprising flexibility in the vicinity of the gatekeeper residue that allows these compounds to overcome a dasatinib-resistant gatekeeper mutation emerging in cSrc.