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Overcoming hurdles in developing successful drugs targeting chemokine receptors

Nature Reviews Immunology volume 11, pages 355–363 (2011)Cite this article

Subjects

Key Points

  • Chemokine receptors are attractive therapeutic targets for inflammatory and autoimmune diseases.

  • It is likely that chemokine receptors could be effectively targeted using small molecule inhibitors.

  • 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.

  • 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.

  • Successful chemokine receptor-based drugs will be enabled by understanding that target selection and sufficient receptor coverage are crucial for therapeutic efficacy.

  • 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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Figure 1: Chemokine and chemokine receptor relationships.
Figure 2: A 'tube map' representation of potential therapeutic targets in the chemokine system.
Figure 3: Levels of pharmacological inhibition of CCR1 necessary for a therapeutic effect in experimental models of inflammation and clinical trials in rheumatoid arthritis.

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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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Authors and Affiliations

  1. Thomas J. Schall is at ChemoCentryx, Inc., 850 Maude Avenue, Mountain View, California 94043, USA. tschall@chemocentryx.com,

    Thomas J. Schall

  2. Amanda E. I. Proudfoot is at Geneva Research Centre, Merck Serono International S.A., 9 chemin des Mines, 1202 Geneva, Switzerland. amanda.proudfoot@merckserono.net,

    Amanda E. I. Proudfoot

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Competing interests

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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