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Selective targeting of the αC and DFG-out pocket in p38 MAPK.

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.
AuthorsSandra 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
JournalEuropean journal of medicinal chemistry (Eur J Med Chem) Vol. 208 Pg. 112721 (Dec 15 2020) ISSN: 1768-3254 [Electronic] France
PMID33035818 (Publication Type: Journal Article)
CopyrightCopyright © 2020 Elsevier Masson SAS. All rights reserved.
Chemical References
  • Phenylurea Compounds
  • Protein Kinase Inhibitors
  • p38 Mitogen-Activated Protein Kinases
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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