ACT-777991 is an Orally Active CXCR3 Antagonist for Immunological Disorders

CXCR3 is a G protein-coupled receptor from the CXC chemokine receptor family. It is mainly expressed in immune cells from the lymphoid lineage, including activated T cells. The CXCR3 receptor is rapidly upregulated following dendritic cell-induced T cell activation. CXCR3 has three ligands including CXCL9, CXCL10, and CXCL11.

They are produced by a number of cell types, such as endothelial cells and monocytes, upon exposure to proinflammatory cytokines (e.g., IFN-γ, TNF-α, and IL-1β).   The binding of a ligand to CXCR3 induces signaling via an increase in intracellular calcium levels, resulting in the migration of CXCR3 cells along the ligand gradient to the site of inflammation. The CXCR3 axis is reported to be upregulated in inflamed tissues of patients with autoimmune diseases. So, it is important for the research of CXCR3.

ACT-777991 is an orally active and selective CXCR3 antagonist

ACT-777991 is a highly potent, insurmountable, and selective CXCR3 antagonist that showed dose-dependent efficacy and target engagement in a mouse model of acute lung inflammation.

In vitro, ACT-777991 inhibits the migration of activated T cells toward CXCL11. Firstly, ACT-777991 inhibits hEGR with an IC50 value of 26 μM in CHO cells. Secondly, ACT-777991 (1 μM; 45 min) is stable in microsomes and hepatocytes across humans, rats, and dogs. Furthermore, ACT-777991 (0.01-1 μM) inhibits the migration of both human and mouse-activated T cells toward CXCL11 with IC50 range of 3.2-64 nM and 4.9-21 nM, respectively. Finally, ACT-777991 (1 nM, 5 nM, 20 nM, and 50 nM) inhibits CXCR3-mediated chemotaxis of human and mouse T cells.

In vivo, ACT-777991 (0.5 mg/kg,1 mg/kg; i.v.; single dose) has low in vivo plasma clearance in male Wistar rats (14/156) or Beagle dogs (5/15). In addition, ACT-777991 (0.006-2 mg/g food; p.o; started 3 days before and 72 h post LPS challenge) dose-dependently inhibits chemotaxis of CXCR3+ T cells in vivo in the mouse model.


[1] Meyer EA, et al. J Med Chem. 2023 Mar 23;66(6):4179-4196.