CXCR3, which belongs to the transmembrane G protein-coupled receptor (GPCR) superfamily, is an inflammatory chemokine receptor. This chemokine receptor can regulate immune cell behavior and promote chemotaxis, cell adhesion as well as mediator release. At the same time, it is mainly expressed on type 1 helper (Th1) CD4+ T cells, effector CD8+ T cells and innate lymphocytes, but also on smooth muscle, epithelial and endothelial cells. CXCR3 has three interferons (IFN)-γ-inducible ligands: CXCT9, CXCT10 and CXCL11. All of them bind and activate CXCR3, recruiting subpopulations of immune cells and thereby causing damage to inflammatory tissues. Overall, the unusual and diverse features of CXCR3 and its ligands form the basis of their association with a myriad of diseases, such as rheumatoid arthritis, multiple sclerosis and diabetes. Therefore, antagonizing CXC3 has become one of the methods to treat these diseases.

CXCR3 antagonists can disrupt CXCR3-mediated signaling by blocking the interaction of CXCR3 with ligands. So, it has also emerged as a new approach to treating a variety of diseases triggered by chemokine receptors, such as atherosclerosis, pulmonary fibrosis, rheumatoid arthritis, multiple sclerosis and other inflammatory diseases.

ACT-660602 is a selective and orally active CXCR3 antagonist.

ACT-660602 exhibits inhibitory activity against CXCR3 with an IC50 value of 204 nM. Also, it has moderate activity against hERG with an IC50 value of 18 μM. Moreover, ACT-660602 (112 nM; 6 h) inhibits cell migration and improves metabolic stability in CD3/CD28-activated primary human T cells. At different concentrations from 5 nM to 500 nM, ACT-660602 is able to bind CXCL10 and CXCL11 ligands non-competitively with a stable IC50 value. Importantly, ACT-660602 (30 mg/kg; p.o.; once daily) exhibits good anti-inflammatory activity in an LPS-induced mouse model of acute lung injury which can significantly reduce the recruitment of CXCR3+ CD8+ T cells in the bronchoalveolar lavage chamber.

In conclusion, ACT-660602 is an orally active, selective chemokine receptor CXCR3 antagonist. It can be used in the study of inflammatory diseases.

[1] J Med Chem. 2022 Aug 10.

[2] Rev. 2015 Jun;26(3):311-27.