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Fast iterative synthetic approach toward identification of novel highly selective p38 MAP kinase inhibitors

DOI: 10.1021/acs.jmedchem.9b01227 DOI Help

Authors: Sandra Röhm (Johann Wolfgang Goethe-University) , Benedict-tilman Berger (Johann Wolfgang Goethe-University) , Martin Schroeder (Structural Genomics Consortium (SGC), Johann Wolfgang Goethe-University) , Apirat Chaikuad (Structural Genomics Consortium (SGC), Johann Wolfgang Goethe-University) , Rob Winkel (Mercachem BV) , Koen F. W. Hekking (Mercachem BV) , Jorg J. C. Benningshof (Mercachem BV) , Gerhard Müller (Gotham Therapeutics) , Roberta Tesch (Structural Genomics Consortium (SGC), Johann Wolfgang Goethe-University) , Mark Kudolo (Eberhard Karls University Tübingen) , Michael Forster (Eberhard Karls University Tübingen) , Stefan Laufer (Eberhard Karls University Tübingen) , Stefan Knapp (Structural Genomics Consortium (SGC), Johann Wolfgang Goethe-University)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry , VOL 62 , PAGES 10757 - 10782

State: Published (Approved)
Published: October 2019
Diamond Proposal Number(s): 10619

Abstract: p38 mitogen-activated protein kinases are key mediators of environmental stress response and are promising targets for treatment of inflammatory diseases and cancer. Numerous efforts have led to the discovery of several potent inhibitors; however, so far no highly selective type-II inhibitors have been reported. We previously identified VPC-00628 as a potent and selective type-II inhibitor of p38α/β with few off-targets. Here we analyzed the chemical building blocks of VPC-00628 that played a key role in achieving potency and selectivity through targeting an inactive state of the kinases induced by a unique folded P-loop conformation. Using a rapid, systematic combinatorial synthetic approach, we identified compound 93 (SR-318) with excellent potency and selectivity for p38α/β, which potently inhibited the TNF-α release in whole blood. SR-318 therefore presents a potent and selective type-II inhibitor of p38α/β that can be used as a chemical probe for targeting this particular inactive state of these two p38 isoforms.

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


Instruments: I04-1-Macromolecular Crystallography (fixed wavelength)