Abstract |
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.
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Authors | Sandra Röhm, Martin Schröder, Jessica E Dwyer, Caroline S Widdowson, Apirat Chaikuad, Benedict-Tilman Berger, Andreas C Joerger, Andreas Krämer, Jule Harbig, Daniel Dauch, Mark Kudolo, Stefan Laufer, Mark C Bagley, Stefan Knapp |
Journal | European journal of medicinal chemistry
(Eur J Med Chem)
Vol. 208
Pg. 112721
(Dec 15 2020)
ISSN: 1768-3254 [Electronic] France |
PMID | 33035818
(Publication Type: Journal Article)
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Copyright | Copyright © 2020 Elsevier Masson SAS. All rights reserved. |
Chemical References |
- Phenylurea Compounds
- Protein Kinase Inhibitors
- p38 Mitogen-Activated Protein Kinases
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Topics |
- Allosteric Regulation
- Allosteric Site
- Animals
- Cell Line, Tumor
- Fluorometry
- HEK293 Cells
- Humans
- Mice
- Microsomes, Liver
(metabolism)
- Phenylurea Compounds
(chemical synthesis, metabolism, pharmacology)
- Protein Binding
- Protein Kinase Inhibitors
(chemical synthesis, metabolism, pharmacology)
- p38 Mitogen-Activated Protein Kinases
(antagonists & inhibitors, chemistry, metabolism)
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