2. Academic Validation
  3. Discovery and exploration of disubstituted [1,2,5]oxadiazolo-[3,4-b]pyrazines as novel C-C chemokine receptor type 5 signaling inhibitors targeting the intracellular allosteric binding pocket

Discovery and exploration of disubstituted [1,2,5]oxadiazolo-[3,4-b]pyrazines as novel C-C chemokine receptor type 5 signaling inhibitors targeting the intracellular allosteric binding pocket

  • Eur J Med Chem. 2025 Jul 5:291:117600. doi: 10.1016/j.ejmech.2025.117600.
Margaux Billen 1,  Sten Reynders 2,  Sandra Claes 3,  Silke Kleinboelting 4,  Jef Rozenski 2,  Radu-George Bulai 2,  Edoardo Rocca 2,  Natalie Z M Homer 5,  Scott P Webster 5,  Tim P Kaminski 4,  Eveline Lescrinier 2,  Dominique Schols 3,  Peter Verwilst 6
Affiliations

Affiliations

  • 1 KU Leuven, Rega Institute for Medical Research, Medicinal Chemistry, Herestraat 49 - Box 1041, 3000, Leuven, Belgium; University of Edinburgh, Mass Spectrometry Core, Centre for Cardiovascular Science, 47 Little France Crescent, EH16 4TJ, Edinburgh, United Kingdom.
  • 2 KU Leuven, Rega Institute for Medical Research, Medicinal Chemistry, Herestraat 49 - Box 1041, 3000, Leuven, Belgium.
  • 3 KU Leuven, Rega Institute for Medical Research, Molecular, Structural and Translational Virology, Herestraat 49 - Box 1041, 3000, Leuven, Belgium.
  • 4 InSingulo AB, Pepparedsleden 1, Mölndal, SE-43183, Sweden.
  • 5 University of Edinburgh, Mass Spectrometry Core, Centre for Cardiovascular Science, 47 Little France Crescent, EH16 4TJ, Edinburgh, United Kingdom.
  • 6 KU Leuven, Rega Institute for Medical Research, Medicinal Chemistry, Herestraat 49 - Box 1041, 3000, Leuven, Belgium. Electronic address: peter.verwilst@kuleuven.be.
PMID: 40222165 DOI: 10.1016/j.ejmech.2025.117600
Abstract

The C-C Chemokine Receptor type 5 is a G protein-coupled receptor expressed on various immune cells, playing a crucial role in inflammation and chemotaxis. Beyond its physiological functions, C-C Chemokine Receptor type 5 is implicated in numerous diseases, including cardiovascular, central nervous system, immune system, and infectious diseases, as well as in the progression of Cancer. The therapeutic potential of C-C Chemokine Receptor type 5 inhibition has been demonstrated by antagonists targeting the extracellular domain, notably maraviroc, a Food and Drug Administration-approved Human Immunodeficiency Virus entry inhibitor. However, challenges such as suboptimal pharmacokinetics and efficacy necessitate new antagonists with unique modes of action. Recent advancements in G protein-coupled receptor structural characterization have identified a novel intracellular allosteric binding site in chemokine receptors. This study introduces a series of disubstituted [1,2,5]oxadiazolo-[3,4-b]pyrazines targeting the intracellular allosteric binding pocket of C-C Chemokine Receptor type 5. Among these, compound 3ad emerged as a promising C-C Chemokine Receptor type 5-selective allosteric antagonist with a half-maximal inhibitory concentration of 1.09 μM and an almost 30-fold selectivity over C-C Chemokine Receptor type 2. Molecular dynamics simulations and a competition assay with a Gαq11 mimetic were used to confirm the intracellular binding mode of these compounds. This novel class of C-C Chemokine Receptor type 5-selective intracellular antagonists offers a foundation for developing molecular tools and therapeutic agents, potentially overcoming the limitations of current extracellular C-C Chemokine Receptor type 5 antagonists.

Keywords

Binding mode validation; CCR5; Intracellular chemokine receptor antagonists; SAR optimization; [1,2,5]oxadiazolo-[3,4-b]pyrazines.

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