A Fluorescent Probe Enables the Discovery of Improved Antagonists Targeting the Intracellular Allosteric Site of the Chemokine Receptor CCR7
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 (<b>4</b>) targeting the CC chemokine receptor CCR7 at an intracellular allosteric site. We demonstrate its experimental power by applying <b>4</b> to identify two improved intracellular CCR7 antagonists, SLW131 (<b>10</b>) and SLW132 (<b>21m</b>), developed by converting two weakly active antagonists into single- or double-digit nanomolar ligands with minimal modifications. The thiadiazoledioxide <b>10</b> was derived from the CCR7 antagonist Cmp2105 by removing a methyl group from the benzamide moiety, while the squaramide <b>21m</b> was obtained from the CXCR1/CXCR2 antagonist and clinical candidate navarixin by replacing the ethyl substituent by a <i>tert</i>-butyl group to engage a lipophilic subpocket. We show that <b>10</b> and <b>21m</b> 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.
Authors
- Matthias Schiedel (ORCID: https://orcid.org/0000-0001-7365-3617)
- Max E. Huber (ORCID: https://orcid.org/0000-0003-3042-0463)
- Isabel Stötzel (ORCID: https://orcid.org/0000-0001-6326-1409)
- Yinshui Chang (ORCID: https://orcid.org/0000-0003-3538-6663)
- Silas Wurnig (ORCID: https://orcid.org/0009-0006-7809-1426)
- Hanna Baltrukevich (ORCID: https://orcid.org/0000-0002-2867-9356)
- Teresa M Steffen (ORCID: https://orcid.org/0009-0009-3311-5051)
- Finn K. Hansen (ORCID: https://orcid.org/0000-0001-9765-5975)
- Peter Kolb (ORCID: https://orcid.org/0000-0003-4089-614X)
- Evi Kostenis (ORCID: https://orcid.org/0000-0001-8284-5514)
- Nicole Merten (ORCID: https://orcid.org/0000-0002-8487-6805)
- Eva Kiermaier (ORCID: https://orcid.org/0000-0001-6165-5738)
- Dirk Baumjohann (ORCID: https://orcid.org/0000-0001-8385-8288)
- Corinna Weiler (ORCID: https://orcid.org/0009-0009-6708-7415)
- René H. L. Klammer
Institutions
- University of Bonn (DE)
- Philipps University of Marburg (DE)
- Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
- University Hospital Bonn (DE)
- Technische Universität Braunschweig (DE)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-02-12
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c02102
- Citations
- 8
- Primary Topic
- Receptor Mechanisms and Signaling
- Type
- article
- Field-Weighted Citation Impact
- 6.45
Funders
- Verband der Chemischen Industrie
- Philipps-Universität Marburg
- Deutsche Forschungsgemeinschaft
- Rheinische Friedrich-Wilhelms-Universität Bonn