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

DOI: 10.1016/j.ejmech.2020.112721 DOI Help

Authors: Sandra Röhm (Johann Wolfgang Goethe University; Buchmann Institute for Molecular Life Sciences and Structural Genomics Consortium (SGC)) , Martin Schroeder (Johann Wolfgang Goethe University; Buchmann Institute for Molecular Life Sciences and Structural Genomics Consortium (SGC)) , Jessica E. Dwyer (University of Sussex) , Caroline S. Widdowson (University of Sussex) , Apirat Chaikuad (ohann Wolfgang Goethe University; Buchmann Institute for Molecular Life Sciences and Structural Genomics Consortium (SGC)) , Benedict-tilman Berger (Johann Wolfgang Goethe University; Buchmann Institute for Molecular Life Sciences and Structural Genomics Consortium (SGC)) , Andreas C. Joerger (Johann Wolfgang Goethe University; Buchmann Institute for Molecular Life Sciences and Structural Genomics Consortium (SGC)) , Andreas Krämer (Johann Wolfgang Goethe University; Buchmann Institute for Molecular Life Sciences and Structural Genomics Consortium (SGC)) , Jule Harbig (University Hospital Tuebingen) , Daniel Dauch (University Hospital Tuebingen; German Cancer Research Consortium (DKTK); University of Tuebingen) , Mark Kudolo (Eberhard Karls University Tübingen) , Stefan Laufer (Eberhard Karls University Tübingen) , Mark C. Bagley (University of Sussex) , Stefan Knapp (Johann Wolfgang Goethe University; Buchmann Institute for Molecular Life Sciences and Structural Genomics Consortium (SGC))
Co-authored by industrial partner: No

Type: Journal Paper
Journal: European Journal Of Medicinal Chemistry , VOL 208

State: Published (Approved)
Published: December 2020
Diamond Proposal Number(s): 10619

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.

Journal Keywords: Selective type-II p38 MAPK inhibitor; Allosteric BIRB fragments; Folded P-loop; Differential scanning fluorimetry (DSF); NanoBRETTM assay

Subject Areas: Chemistry, Biology and Bio-materials, Medicine


Instruments: I03-Macromolecular Crystallography

Other Facilities: 14.3 at BESSY; X06SA at SLS

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