Targeting a Glutamic Acid in PDEδ with Fluoromethyl-Aryl Electrophiles Impairs K-Ras Signaling
Year: 2026
Type: article
Abstract: High Resolution Image Download MS PowerPoint Slide 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 Kras G12D -driven lung adenocarcinoma, Deltafluorine treatment significantly reduces tumor volume.
Source: Journal of Medicinal Chemistry
Authors: Ruirui Zhang, Maxim A. Huetzen, Aylin Binici, Pablo Martín-Gago, Raphael Gasper, Elena Rudashevskaya, Jie Liu, Chinta Nagaraju, Elena S. Reckzeh, Alana S. T. Stuedle, Ann-Sophie Hopff, Andrea Mesaros, Anke Unger, Melanie Thelen, Petra Janning, H. Christian Reinhardt, Slava Ziegler, Ron D. Jachimowicz, Herbert Waldmann
Institutions: Max Planck Institute of Molecular Physiology, Max Planck Society, University of Cologne, Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases, Max Planck Institute for Biology of Ageing, TU Dortmund University, Lead Discovery Center (Germany), Essen University Hospital, University of Duisburg-Essen
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $4,500
Funders: Deutsche Forschungsgemeinschaft, European Synchrotron Radiation Facility, Bundesministerium für Bildung und Forschung, Max-Planck-Gesellschaft, Deutsche Krebshilfe, Institut National Du Cancer, Universität zu Köln, Universität Duisburg-Essen, Deutschen Konsortium für Translationale Krebsforschung, Center for Molecular Medicine Cologne, University of Cologne
Awards: G1258522988, G1773586305, FOR 5504: Physiologische Ursachen und Konsequenzen der Genominstabilität, G3269623647, SFB 1399: Mechanismen der MedikamentenEmpfindlichkeit und Resistenz beim kleinzelligen Bronchialkarzinom, G4874733847, G5489270881, G579307425, G5905007886, G5990751553, InCa - Ein systemischer Ansatz zur Untersuchung von heterotypischen Wechselwirkungen von Lungenkrebszellen mit ihrer Mikroumgebung - Teilvorhaben UK Köln, SP0,1,2a,3,4,6, G6723498533, SFB 1530: Aufklärung und Targeting pathogener Mechanismen bei BZellNeoplasien, G7810882343, SFB 1430: Molekulare Mechanismen von Zellzustandsübergängen, G8927102669
OpenAlex ID: W7119228870