2. Academic Validation
  3. A Fluorescent Probe Enables the Discovery of Improved Antagonists Targeting the Intracellular Allosteric Site of the Chemokine Receptor CCR7

A Fluorescent Probe Enables the Discovery of Improved Antagonists Targeting the Intracellular Allosteric Site of the Chemokine Receptor CCR7

  • J Med Chem. 2025 Feb 27;68(4):4308-4333. doi: 10.1021/acs.jmedchem.4c02102.
Silas L Wurnig 1,  Max E Huber 2,  Corinna Weiler 3,  Hanna Baltrukevich 4,  Nicole Merten 3,  Isabel Stötzel 5,  Teresa Steffen 6,  Yinshui Chang 6,  René H L Klammer 1,  Dirk Baumjohann 6,  Eva Kiermaier 5,  Peter Kolb 4,  Evi Kostenis 3,  Matthias Schiedel 2 7,  Finn K Hansen 1
Affiliations

Affiliations

  • 1 Department of Pharmaceutical & Cell Biological Chemistry, Pharmaceutical Institute, University of Bonn, An der Immenburg 4, Bonn 53121, Germany.
  • 2 Department of Chemistry and Pharmacy, Medicinal Chemistry, Friedrich-Alexander-University Erlangen-Nürnberg, Nikolaus-Fiebiger-Straße 10, Erlangen 91058, Germany.
  • 3 Molecular, Cellular and Pharmacobiology Section, Institute for Pharmaceutical Biology, University of Bonn, Nussallee 6, Bonn 53115, Germany.
  • 4 Department of Pharmaceutical Chemistry, University of Marburg, Marbacher Weg 8, Marburg 35037, Germany.
  • 5 Life and Medical Sciences (LIMES) Institute, Immune and Tumor Biology, University of Bonn, Bonn 53115, Germany.
  • 6 Medical Clinic III for Oncology, Hematology, Immuno-Oncology and Rheumatology, University Hospital Bonn, University of Bonn, Venusberg-Campus 1, Bonn 53127, Germany.
  • 7 Institute of Medicinal and Pharmaceutical Chemistry, Technische Universität Braunschweig, Beethovenstraße 55, Braunschweig 38106, Germany.
PMID: 39937529 DOI: 10.1021/acs.jmedchem.4c02102
Abstract

Intracellular ligands of G protein-coupled receptors (GPCRs) are gaining significant interest in drug discovery. Here, we report the development of the fluorescent ligand Mz437 (4) targeting the CC Chemokine Receptor CCR7 at an intracellular allosteric site. We demonstrate its experimental power by applying 4 to identify two improved intracellular CCR7 antagonists, SLW131 (10) and SLW132 (21m), developed by converting two weakly active antagonists into single- or double-digit nanomolar ligands with minimal modifications. The thiadiazoledioxide 10 was derived from the CCR7 Antagonist Cmp2105 by removing a methyl group from the benzamide moiety, while the squaramide 21m was obtained from the CXCR1/CXCR2 Antagonist and clinical candidate navarixin by replacing the ethyl substituent by a tert-butyl group to engage a lipophilic subpocket. We show that 10 and 21m qualify to probe CCR7 biology in recombinant and primary immune cells and expect our novel probes to facilitate the design of next-generation intracellular CCR7 ligands.

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