2. Academic Validation
  3. A twist in the tale: shifting from covalent targeting of a tyrosine in JAK3 to a lysine in MK2

A twist in the tale: shifting from covalent targeting of a tyrosine in JAK3 to a lysine in MK2

  • RSC Med Chem. 2025 Aug 1;16(10):4906-4919. doi: 10.1039/d5md00440c.
Laura Hillebrand 1 2,  Guiqun Wang 3 4 5,  Alexander Rasch 6,  Benedikt Masberg 7,  Apirat Chaikuad 3 4 5,  Thales Kronenberger 8 9 10,  Ellen Günther 6,  Michael Forster 2 6,  Antti Poso 10 11,  Michael Lämmerhofer 7,  Stefan A Laufer 2 6 11,  Stefan Knapp 3 4 5,  Matthias Gehringer 1 2 6
Affiliations

Affiliations

  • 1 Faculty of Medicine, Institute of Biomedical Engineering, Department for Medicinal Chemistry, Eberhard Karls University Tübingen Auf der Morgenstelle 8 D-72076 Tübingen Germany matthias.gehringer@uni-tuebingen.de.
  • 2 Cluster of Excellence iFIT (EXC 2180) "Image-Guided & Functionally Instructed Tumor Therapies", Eberhard Karls University Tübingen D-72076 Tübingen Germany.
  • 3 Institute for Pharmaceutical Chemistry, Johann Wolfgang Goethe-University Frankfurt Max-von-Laue-Str. 9 D-60438 Frankfurt am Main Germany.
  • 4 Structure Genomics Consortium Buchmann Institute for Molecular Life Sciences, Johann Wolfgang Goethe-University Frankfurt Max-von-Laue-Str. 15 D-60438 Frankfurt am Main Germany.
  • 5 German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), DKTK site Frankfurt-Mainz D-69120 Heidelberg Germany.
  • 6 Institute of Pharmaceutical Sciences, Department of Pharmaceutical/Medicinal Chemistry, Eberhard Karls University Tübingen Auf der Morgenstelle 8 D-72076 Tübingen Germany.
  • 7 Pharmaceutical (Bio-)Analysis, Institute of Pharmaceutical Sciences, Department of Pharmaceutical/Medicinal Chemistry, Eberhard Karls University Tübingen Auf der Morgenstelle 8 D-72076 Tübingen Germany.
  • 8 Interfaculty Institute of Microbiology and Infection Medicine (IMIT), Eberhard Karls University Tübingen Tübingen Germany.
  • 9 Partner-site Tübingen, German Center for Infection Research (DZIF) D-72076 Tübingen Germany.
  • 10 Faculty of Health Sciences, School of Pharmacy, University of Eastern Finland P.O. Box 1627 FI-70211 Kuopio Finland.
  • 11 Tübingen Center for Academic Drug Discovery & Development (TüCAD2), Eberhard Karls University Tübingen D-72076 Tübingen Germany.
PMID: 40756524 DOI: 10.1039/d5md00440c
Abstract

While cysteine targeting in kinases is well established and widely used, covalent interactions with other Amino acids remain much less explored. We aimed to develop covalent inhibitors targeting tyrosine residues in the protein kinases JAK3 and MK2 using structure-based design principles to generate small sets of ligands containing tyrosine-reactive sulfonyl fluoride and the less-explored fluorosulfate warheads. While the JAK3 inhibitors failed to achieve covalent binding, the fluorosulfate-bearing MK2 inhibitor 42, which had been designed as an allosteric binder, unexpectedly formed a bond with the "catalytic" lysine, additionally uncovering a unique interaction at the hinge region. This highlights the untapped potential of fluorosulfates and provides a rare example of the use of this electrophile for lysine targeting in kinases. Our results highlight the limitations of traditional design methods and support the integration of fragment/lead-like covalent library screening to discover unanticipated interactions.

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