ArticleMolecular pharmacology2025
Inhibition of constitutive activity of the atypical chemokine receptor 3 by the small-molecule inverse agonist VUF16840.
Article in Molecular pharmacology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.
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Who cites it
3 citing papers in PubMed.
- Identification of Entacapone as a Novel β-Arrestin 1 Biased Antagonist of CXCR7.Molecules (Basel, Switzerland) · 2026Article
- Atypical GPCR Activation Resolved by Nanobody Engineering.bioRxiv : the preprint server for biology · 2026Article
- Constitutive activity of an atypical chemokine receptor revealed by inverse agonistic nanobodies.Nature communications · 2025Article
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Authors and funding
15 authors.
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Abstract
The atypical chemokine receptor 3 (ACKR3) has emerged as a promising drug target for the treatment of cancer, cardiovascular, and autoimmune diseases. In this study, we present the pharmacological characterization of VUF16840, the first small-molecule inverse agonist of ACKR3. VUF16840 effectively displaces CXC chemokine ligand 12 binding to ACKR3 and inhibits chemokine-induced β-arrestin2 recruitment in a concentration-dependent manner. Furthermore, VUF16840 stabilizes the inactive conformation of ACKR3, as demonstrated by its ability to suppress constitutive recruitment of downstream effector proteins. This inverse agonism alters ACKR3 constitutive trafficking, leading to receptor enrichment at the plasma membrane and inhibition of intracellular CXC chemokine ligand 12 uptake. Importantly, VUF16840 exhibits high selectivity for ACKR3 over a broad panel of human chemokine receptors. These findings establish VUF16840 as a potent and selective ACKR3 inverse agonist capable of modulating constitutive and chemokine-induced signaling and internalization events. As such, VUF16840 represents a valuable pharmacological tool for exploring the molecular and translational roles of ACKR3 in both physiologic and pathologic contexts. SIGNIFICANCE STATEMENT: A small molecule inverse agonist of the atypical chemokine receptor 3 (ACKR3), named VUF16840, is characterized in this work. It was shown that VUF16840 was able to inhibit basal as well as ligand-induced ACKR3 activation and, moreover, inhibits the scavenging function of ACKR3.
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