Overcoming hurdles in developing successful drugs targeting chemokine receptors

• Published in: Nature reviews. Immunology Vol. 11; no. 5; pp. 355 - 363
• Main Authors: Schall, Thomas J, Proudfoot, Amanda E. I
• Format: Journal Article Book Review
• Language: English
• Published: London Nature Publishing Group UK 01-05-2011; Nature Publishing Group
• Subjects: 631/154/309/2144; 631/250/249/2510; 692/700/565/1436/2185; 98; Animals; Anti-inflammatory drugs; Arthritis, Rheumatoid - drug therapy; Arthritis, Rheumatoid - immunology; Autoimmune diseases; Autoimmune Diseases - immunology; Biomedical and Life Sciences; Biomedicine; Chemokine receptors; Chemokines; Chemokines - genetics; Chemokines - metabolism; Chemokines - physiology; Drug Discovery; Drug dosages; Drug therapy; Health aspects; HIV; HIV Infections - drug therapy; HIV Infections - immunology; Human immunodeficiency virus; Humans; Immunology; Inflammation; Inflammation - drug therapy; Inflammation - immunology; Inflammatory diseases; Ligands; Mice; Molecular Targeted Therapy; opinion-2; Pathology; Physiological aspects; Receptors, CCR1 - antagonists & inhibitors; Receptors, Chemokine - antagonists & inhibitors; Receptors, Chemokine - immunology; Receptors, Chemokine - metabolism; Rheumatoid arthritis; Stem cells; United States
• ISSN: 1474-1733; 1474-1741
• DOI: 10.1038/nri2972

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.
Despite the frequently proposed 'redundancy' of the chemokine system, these authors put forward the opinion that targeting a single chemokine receptor can be effective in treating inflammatory disease provided that the
in vivo
potency is sufficient.
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.