The FDA-approved CDK4/6 inhibitor Abemaciclib is a potent agonist of the β-arrestin-biased atypical chemokine receptor ACKR3

Abemaciclib is a nanomolar agonist of the β-arrestin–biased GPCR ACKR3, inhibiting CXCL12 binding and promoting β-arrestin recruitment and internalization.

• Why it matters: ACKR3 regulates chemokine availability and is linked to cancer, inflammation, autoimmunity, cardiovascular disease, and CNS repair, but few drug-like tools exist to modulate it.
• What they did: Using a NanoBRET fluorescent chemokine-binding competition screen of 2,342 FDA-approved compounds, the study profiled abemaciclib versus other CDK4/6 inhibitors and performed binding, functional, NMR, and 3.2 Å cryo-EM structural analyses.
• The result: Abemaciclib selectively activated ACKR3 (not CXCR4/CXCR5), blocked CXCL11/CXCL12 uptake in vitro, and increased plasma CXCL12 after oral dosing in mice, supporting in vivo target engagement.

AI summary of the abstract · may contain errors · not medical advice · read the paper.