2. Academic Validation
  3. Structure-activity relationship study of navarixin analogues as dual CXCR2 and CCR7 antagonists

Structure-activity relationship study of navarixin analogues as dual CXCR2 and CCR7 antagonists

  • Bioorg Chem. 2025 Jun 1:159:108423. doi: 10.1016/j.bioorg.2025.108423.
Anže Meden 1,  Sandra Claes 2,  Tom Van Loy 2,  Maša Zorman 1,  Matic Proj 1,  Dominique Schols 2,  Stanislav Gobec 3,  Steven De Jonghe 4
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Ljubljana, Askerceva 7, 1000 Ljubljana, Slovenia.
  • 2 KU Leuven, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Molecular, Structural and Translational Virology Research Group, Herestraat 49, box 1043, 3000 Leuven, Belgium.
  • 3 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Ljubljana, Askerceva 7, 1000 Ljubljana, Slovenia. Electronic address: Stanislav.Gobec@ffa.uni-lj.si.
  • 4 KU Leuven, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Molecular, Structural and Translational Virology Research Group, Herestraat 49, box 1043, 3000 Leuven, Belgium. Electronic address: steven.dejonghe@kuleuven.be.
PMID: 40179581 DOI: 10.1016/j.bioorg.2025.108423
Abstract

Despite the promise of the human Chemokine Receptor 7 (CCR7) as drug target for the treatment of Cancer metastasis and autoimmune diseases, there are no potent and selective CCR7 antagonists known in literature. In this work, a 1,2,5-thiadiazole 1,1-dioxide with low μM activity as a CXCR2 and CCR7 Antagonist was selected as starting point for a structure-activity relationship study. The replacement of the central thiadiazole dioxide motif with squaramide led to low nanomolar CCR7 antagonism. Additional systematic structural variations afforded various squaramide analogues that displayed potent CCR7 antagonism in a calcium mobilization assay with IC50 values in the low nM range. Unfortunately, the same compounds also displayed potent CXCR2 antagonistic activity and should therefore be considered as dual CCR7/CXCR2 antagonists.

Keywords

1,2,5-thiazole 1,1-dioxide; Antagonist; CCR7; CXCR2; Navarixin.

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