Discovery of Clinical Candidate ACT-777991, a Potent CXCR3 Antagonist for Antigen-Driven and Inflammatory Pathologies

The CXCR3 chemokine receptor is a G protein-coupled receptor mainly expressed on immune cells from the lymphoid lineage, including activated T cells. Binding of its inducible chemokine ligands CXCL9, CXCL10, and CXCL11 leads to downstream signaling events and the migration of activated T cells to sites of inflammation. Herein, we report the third part of our CXCR3 antagonist program in the field of autoimmunity, culminating in the discovery of the clinical compound ACT-777991 (8a). A previously disclosed advanced molecule was exclusively metabolized by the CYP2D6 enzyme, and options to address the issue are described. 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. The excellent properties and safety profile warranted progress in the clinics.CXCR3趋化因子受体（CXCR3 chemokine receptor）是一类主要表达于淋巴系免疫细胞（包括活化T细胞）的G蛋白偶联受体（G protein-coupled receptor）。其诱导型趋化因子配体CXCL9、CXCL10与CXCL11结合该受体后，可触发下游信号转导事件，并介导活化T细胞向炎症部位迁移。本文报道了我们在自身免疫领域开展的CXCR3拮抗剂研究项目的第三部分，最终成功发现了临床化合物ACT-777991（8a）。此前公开披露的一款晚期研发候选分子仅能由CYP2D6酶（CYP2D6 enzyme）代谢，本文同时描述了针对该代谢问题的解决方案。ACT-777991是一款强效、不可逆且选择性的CXCR3拮抗剂，在急性肺炎症小鼠模型中展现出剂量依赖性的药效与靶点结合（target engagement）活性。其优异的药理学特性与安全性谱支持其推进至临床研究阶段。