Active Cancer Diabetes, Hormones & Metabolism

Exploring Allostery at the Atypical Chemokine Receptor 3 (ACKR3)

Funder Wellcome Charity-funded
Recipient organisation University of Nottingham
Funding Not disclosed
Period Oct 2025 — Sept 2028

In plain English

AI plain-English summary

A drug target called ACKR3 sits on the surface of cells and controls how they move, but the standard approach to blocking it with drugs often fails because the body’s own signalling molecules swamp the binding site. This matters because ACKR3 is implicated in inflammatory diseases, metastatic cancers, and neurodegenerative disorders. The problem is that the usual drug-binding spot—the orthosteric site—is constantly occupied by high concentrations of the natural chemokine, especially in diseased tissue. The researchers are instead targeting a separate, unexplored pocket inside the cell, using a synthetic antibody fragment called CID24 as a starting point. They will combine computational modelling, chemical synthesis, and pharmacological assays to design new intracellular allosteric ligands (IALs) that bind this hidden site. If successful, this work is primarily fundamental science. It will clarify how ACKR3 works at a molecular level and provide tools to study its biology. Deeper understanding of this receptor could eventually underpin new therapeutic strategies for conditions where cell migration goes wrong—such as cancer metastasis or chronic inflammation—but the immediate goal is to map the receptor’s inner workings, not to produce a drug.

View original technical description
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.

View the original record at the funder ↗

Researchers

Rana Dawood (EPMC Awardee)

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Original classification

PhD Studentship (Basic)

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