2. Academic Validation
  3. Targeting a Glutamic Acid in PDEδ with Fluoromethyl-Aryl Electrophiles Impairs K-Ras Signaling

Targeting a Glutamic Acid in PDEδ with Fluoromethyl-Aryl Electrophiles Impairs K-Ras Signaling

  • J Med Chem. 2026 Jan 22;69(2):964-981. doi: 10.1021/acs.jmedchem.5c02082.
Ruirui Zhang 1,  Maxim A Huetzen 2 3 4 5,  Aylin Binici 1 6,  Pablo Martín-Gago 1,  Raphael Gasper 7,  Elena Rudashevskaya 1,  Jie Liu 1,  Chinta Nagaraju 1,  Elena S Reckzeh 1,  Alana S T Stuedle 2 3 4 5,  Ann-Sophie Hopff 2 3 4 5,  Andrea Mesaros 8,  Anke Unger 9,  Melanie Thelen 2 3 4 5,  Petra Janning 1,  H Christian Reinhardt 10,  Slava Ziegler 1,  Ron D Jachimowicz 2 3 4 5,  Herbert Waldmann 1 6
Affiliations

Affiliations

  • 1 Department of Chemical Biology, Max Planck Institute of Molecular Physiology, Otto-Hahn-Street 11, Dortmund 44227, Germany.
  • 2 Max Planck Research Group Mechanisms of DNA Repair, Max Planck Institute for Biology of Ageing, Cologne 50931, Germany.
  • 3 Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf (CIO ABCD), University of Cologne, Cologne 50931, Germany.
  • 4 Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases, University of Cologne, Cologne 50931, Germany.
  • 5 Center for Molecular Medicine Cologne, University of Cologne, Cologne 50931, Germany.
  • 6 Faculty of Chemistry and Chemical Biology, Technical University Dortmund, Otto-Hahn-Street 6, Dortmund 44221, Germany.
  • 7 Crystallography and Biophysics Facility, Max Planck Institute of Molecular Physiology, Otto-Hahn-Street 11, Dortmund 44227, Germany.
  • 8 Phenotyping Core Facility, Max Planck Institute for Biology of Ageing, Cologne 50931, Germany.
  • 9 Lead Discovery Center GmbH, Otto-Hahn-Str. 15, Dortmund D-44227, Germany.
  • 10 Department of Hematology and Stem Cell Transplantation, University Hospital Essen, West German Cancer Center, German Cancer Consortium Partner Site Essen, Center for Molecular Biotechnology, University of Duisburg-Essen, Hufelandstraße 55, Essen 45147, Germany.
PMID: 41499451 DOI: 10.1021/acs.jmedchem.5c02082
Abstract

For targeted covalent modification at low-reactivity carboxylates with biocompatible electrophiles, new approaches are in high demand. Engineering of the HaloTag protein facilitates such a covalent reaction between chloroalkanes and an aspartate residue. We demonstrate that conversely, engineering stable ligands can also enable covalent targeting of an acid residue in a protein binding site. Using the chaperone PDEδ, which shuttles lipidated oncoproteins and thereby mediates their signaling activity, we show that equipping noncovalent inhibitors with a benzyl fluoride-based electrophile leads to covalent modification of a specific glutamate p.E88 in the ligand binding site. The best inhibitor, Deltafluorine, embodies a 3-fluoromethyl-pyridyl group and is stable to nucleophiles like glutathione, phosphate, acetate, and citrate. In cells, Deltafluorine combines noncovalent and covalent reactivity to demonstrate distinct cellular profiles and inhibits signaling through the MAP-kinase and Akt-mTOR pathways. In an autochthonous mouse model of highly aggressive KrasG12D-driven lung adenocarcinoma, Deltafluorine treatment significantly reduces tumor volume.

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