Exploring Allostery at the Atypical Chemokine Receptor 3 (ACKR3) (360G-Wellcome-337135_Z_25_Z)

The atypical chemokine receptor 3 (ACKR3) is a G protein-coupled receptor (GPCR) important in the regulation of cellular migration, mediating chemokine gradients via an internalisation-driven sequestration mechanism. In recent years, ACKR3 has emerged as an axiomatic target in inflammatory diseases, metastatic cancers, and neurodegenerative disorders. To date, research efforts have focused on therapeutically targeting the ACKR3 orthosteric chemokine- recognition binding site. However, targeting the orthosteric binding site is therapeutically challenging as the drugs need to compete with elevated concentrations of the endogenous chemokine in inflammatory diseased states, or within cancer cells. Therefore, targeting a topographically distinct binding site using allosteric modulators is increasingly attractive. We are investigating an unexplored intracellular allosteric pocket of ACKR3, for the discovery of novel intracellular allosteric ligands (IALs). Previous structural studies have identified CID24 as a synthetic antibody fragment (Fab) that stabilises the cytosolic face of ACKR3 in the active state. A cross-disciplinary approach comprising computational modelling, chemical synthesis, and pharmacological assay development will enable the development of novel ACKR3 IALs inspired by CID24. These IALs will further the understanding of ACKR3 biology and underpin the future therapeutic exploitation of this receptor. Key Words: ACKR3, CXCR7, GPCR, chemokine receptor, inflammation, cancer, metastasis, neurodegeneration, allosteric, IALs.