Key Points
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Chemokine receptors are attractive therapeutic targets for inflammatory and autoimmune diseases.
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It is likely that chemokine receptors could be effectively targeted using small molecule inhibitors.
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Drugs targeting various chemokine receptors have been approved for non-inflammatory conditions, but so far there are no such drugs for autoimmune or inflammatory disease.
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The current lack of successful drugs targeting chemokine receptors in autoimmune and inflammatory diseases should not be attributed to the so-called 'redundancy' of the chemokine system.
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Successful chemokine receptor-based drugs will be enabled by understanding that target selection and sufficient receptor coverage are crucial for therapeutic efficacy.
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Clinical trials designed according to these principles will establish the validity of therapeutic interventions that inhibit this receptor class.
Abstract
Chemokines and their receptors are central to the inflammatory process and are attractive therapeutic targets. Drugs that inhibit chemokine receptors are approved for the treatment of HIV infection and for stem cell mobilization, but none have been approved yet for the treatment of inflammatory and/or autoimmune diseases. We analyse the challenges of developing chemokine receptor antagonists, and propose that inappropriate target selection and ineffective dosing, not the 'redundancy' of the chemokine system, are the main barriers to their use as anti-inflammatory therapies. We highlight evidence suggesting that chemokine receptor inhibition will prove to be an effective therapy in inflammatory diseases.
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Acknowledgements
We are indebted to our colleagues D. Dairaghi, H. Wang, J. Powers and particularly J. Jaen for their work in assessing the 'true potencies' of chemokine receptor antagonists in vivo and in modelling receptor coverage requirements for therapeutic efficacy, as well as for insightful discussions.
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Thomas J. Schall is an employee and shareholder of ChemoCentryx, which has an interest in developing chemokine-based therapeutics. He is an inventor on patents for chemokine receptor antagonists, antibodies and chemokine-based immune modulators.
Amanda E. I. Proudfoot is an employee of Merck Serono SA and is an inventor on patents for chemokine receptor inhibitors, modified chemokine antagonists and chemokine binding proteins.
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Schall, T., Proudfoot, A. Overcoming hurdles in developing successful drugs targeting chemokine receptors. Nat Rev Immunol 11, 355–363 (2011). https://doi.org/10.1038/nri2972
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DOI: https://doi.org/10.1038/nri2972
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