EJMC 2020 manuscript_accepted version.pdf (1.99 MB)
Selective targeting of the aC and DFG-out pocket in p38 MAPK
journal contribution
posted on 2023-06-09, 22:52 authored by 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 BagleyMark Bagley, Stefan KnappThe 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 aC-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.
History
Publication status
- Published
File Version
- Accepted version
Journal
European Journal of Medicinal ChemistryISSN
0223-5234Publisher
ElsevierExternal DOI
Volume
208Page range
1-35Article number
a112721Department affiliated with
- Chemistry Publications
Full text available
- Yes
Peer reviewed?
- Yes
Legacy Posted Date
2021-01-21First Open Access (FOA) Date
2021-08-21First Compliant Deposit (FCD) Date
2021-01-21Usage metrics
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