1208234-80-3Relevant academic research and scientific papers
Selective targeting of the αC and DFG-out pocket in p38 MAPK
R?hm, Sandra,Schr?der, Martin,Dwyer, Jessica E.,Widdowson, Caroline S.,Chaikuad, Apirat,Berger, Benedict-Tilman,Joerger, Andreas C.,Kr?mer, Andreas,Harbig, Jule,Dauch, Daniel,Kudolo, Mark,Laufer, Stefan,Bagley, Mark C.,Knapp, Stefan
, (2020)
The p38 MAPK cascade is a key signaling pathway linked to a multitude of physiological functions and of central importance in inflammatory and autoimmune diseases. Although studied extensively, little is known about how conformation-specific inhibitors alter signaling outcomes. Here, we have explored the highly dynamic back pocket of p38 MAPK with allosteric urea fragments. However, screening against known off-targets showed that these fragments maintained the selectivity issues of their parent compound BIRB-796, while combination with the hinge-binding motif of VPC-00628 greatly enhanced inhibitor selectivity. Further efforts focused therefore on the exploration of the αC-out pocket of p38 MAPK, yielding compound 137 as a highly selective type-II inhibitor. Even though 137 is structurally related to a recent p38 type-II chemical probe, SR-318, the data presented here provide valuable insights into back-pocket interactions that are not addressed in SR-318 and it provides an alternative chemical tool with good cellular activity targeting also the p38 back pocket.
P38 MAP KINASE INHIBITORS
-
Page/Page column 53, (2011/10/31)
There is provided a compound of formula (I): wherein: J represents (A): or (B): compositions comprising same, processes for preparing said compounds and use thereof in treatment, particularly in the treatment of inflammatory disease, such as asthma, COPD and 15 rheumatoid arthritis.
