2. Academic Validation
  3. Fast Iterative Synthetic Approach toward Identification of Novel Highly Selective p38 MAP Kinase Inhibitors

Fast Iterative Synthetic Approach toward Identification of Novel Highly Selective p38 MAP Kinase Inhibitors

  • J Med Chem. 2019 Dec 12;62(23):10757-10782. doi: 10.1021/acs.jmedchem.9b01227.
Sandra Röhm 1 2,  Benedict-Tilman Berger 1 2,  Martin Schröder 1 2,  Apirat Chaikuad 1 2,  Rob Winkel 3,  Koen F W Hekking 3,  Jorg J C Benningshof 3,  Gerhard Müller 4,  Roberta Tesch 1 2,  Mark Kudolo 5,  Michael Forster 5,  Stefan Laufer 5,  Stefan Knapp 1 2
Affiliations

Affiliations

  • 1 Institute for Pharmaceutical Chemistry , Johann Wolfgang Goethe-University , Max-von-Laue-Str. 9 , D-60438 Frankfurt am Main , Germany.
  • 2 Structural Genomics Consortium (SGC), Buchmann Institute for Life Sciences , Johann Wolfgang Goethe-University , Max-von-Laue-Str. 15 , D-60438 Frankfurt am Main , Germany.
  • 3 Mercachem BV , Kerkenbos 1013 , 6546 BB Nijmegen , The Netherlands.
  • 4 Gotham Therapeutics , 430 East 29th Street , Alexandria Center, New York , New York 10016 , United States.
  • 5 Department of Pharmaceutical/Medicinal Chemistry , Eberhard Karls University Tübingen , Auf der Morgenstelle 8 , 72076 Tübingen , Germany.
PMID: 31702918 DOI: 10.1021/acs.jmedchem.9b01227
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.

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