CCR4 is a C-C chemokine receptor and a therapeutic target for malignancies, functioning as a receptor for the chemokines ccl17 and ccl22. It is targeted by antagonists and has been clinically validated in adult T cell leukemia/lymphoma, cutaneous T cell lymphoma, and other cancers. Structural work has now analyzed CCR4 in the apo state and in complex with four inhibitors, clarifying how both orthosteric and allosteric modulation occurs. In particular, tivumecirnon and zelnecirnon bind the orthosteric site, azd2098 and gsk2239633a occupy an allosteric site, and mogamulizumab binds the N-terminal region of the receptor. These findings support CCR4 as a druggable chemokine receptor with multiple inhibition modes and reinforce its role in oncology.
Malignancy
- A 2026 PNAS structural study (PMID:41950080) showed CCR4 in apo form and bound to four antagonists, supporting its use as a clinically validated target in adult T cell leukemia/lymphoma and cutaneous T cell lymphoma. (PMID:41950080)
- The study defined two pharmacologic modes at CCR4: orthosteric binding by tivumecirnon and zelnecirnon, and allosteric binding by azd2098 and gsk2239633a. (PMID:41950080)
- mogamulizumab was shown to bind the N-terminal region of CCR4, providing a distinct antibody-based mechanism of receptor modulation. (PMID:41950080)
- The structural analysis of four inhibitors expands the mechanistic basis for targeting CCR4 in other malignancies beyond T cell lymphomas. (PMID:41950080)
Chemokine signaling
- CCR4 is the receptor for ccl17 and ccl22, placing it in chemokine-mediated signaling pathways relevant to immune cell trafficking. (PMID:41950080)
- The receptor’s modulation by antagonists highlights its role as a chemokine receptor targeted by small molecules and antibodies. (PMID:41950080)