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

Röhm, Sandra, Schröder, Martin, Dwyer, Jessica E, Widdowson, Caroline S, Chaikuad, Apirat, Berger, Benedict-Tilman, Joerger, Andreas C, Krämer, Andreas, Harbig, Jule, Dauch, Daniel, Kudolo, Mark, Laufer, Stefan, Bagley, Mark C and Knapp, Stefan (2020) Selective targeting of the αC and DFG-out pocket in p38 MAPK. European Journal of Medicinal Chemistry, 208. a112721 1-35. ISSN 0223-5234

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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.

Item Type: Article
Schools and Departments: School of Life Sciences > Chemistry
SWORD Depositor: Mx Elements Account
Depositing User: Mx Elements Account
Date Deposited: 21 Jan 2021 14:38
Last Modified: 21 Aug 2021 01:00

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