Aurelien Zarca, Ilze Adlere, Cristina P Viciano, Marta Arimont-Segura, Max Meyrath, Icaro A Simon, Jan Paul Bebelman, Dennis Laan, Hans G J Custers, Elwin Janssen, Kobus L K Versteegh, Maurice Buzink, Desislava Nesheva, Reggie Bosma, Iwan J P de Esch, Henry Vischer, Maikel Wijtmans, Martyna Szpakowska, Andy Chevigné, Carsten Hoffmann, Chris de Graaf, Barbara A Zarzycka, Albert D Windhorst, Martine J Smit, Rob Leurs
Atypical chemokine receptor 3 (ACKR3 is considered to be an interesting drug target. In this study we report on the synthesis, pharmacological characterization and radiolabeling of VUF15485, a new small-molecule agonist. VUF15485 binds with nanomolar affinity (pIC50 = 8.3) to human ACKR3, as measured in [125I]CXCL12 competition experiments. Moreover, in a BRET-based β-arrestin2 recruitment assay VUF15485 acts as an ACKR3 agonist with high potency (pEC50 = 7.6) and shows a similar extent of receptor activation compared to CXCL12 when using a newly developed, FRET-based ACKR3 conformational sensor...
February 12, 2024: Molecular Pharmacology