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Chemokine receptor antagonists: overcoming developmental hurdles
Richard Horuk
Abstract | Chemokine receptors have a key role in the pathogenesis of auto
immune diseases, inflammation and viral infection. However, with the exception of selective CCR5 antagonists for HIV, the promise of obtaining new therapeutics related to chemokine receptors has not yet been realized. This article highlights some of the recent failures in the clinical trials of chemokine receptor antagonists and explores possible reasons as to why this might have occurred. Such reasons include the lack of predictability of animal models and redundancy of the target. A potential solution could be to develop drugs that target more than one receptor known as polypharmacology which could be a novel way to generate effective thera peutics.
The human immune system has evolved to effectively eliminate pathogenic organisms that it encounters. Usually this system of defence works extremely well in protecting the host, but can sometimes malfunction, leading to autoimmune diseases such as rheumatoid arthritis, asthma, diabetes, inflammatory bowel disease and multiple sclerosis. These conditions pose an increasing health burden on society and affect millions of individuals each year. Indeed, estimates for 2006 suggest a worldwide market size in excess of US$21 billion per year for autoimmune diseases as a class1. Pharmaceutical and biotechnology companies have risen to the challenge and poured billions of dollars into research and development with the aim of identifying safe and effective drugs to treat these diseases. Programmes centred on inhibiting the activity of chemokine receptors have been a major focus of interest in this area because of their role in the pathogenesis of autoimmune diseases2
(BOX 1; TABLE 1). Unfortunately, the promise
of obtaining novel and effective therapeutics from chemokine receptor antagonist programmes has not been fully realized. Instead, there have been several failedPhase II clinical studies, which have tempered the initial enthusiasm for these proteins as drug targets.
There are various reasons for why a drug can fail in clinical trials, including not having reliable animal models of the disease that is being targeted, not having a good method of measuring the amount of active drug (that is, a pharmacodynamic assay) and redundancy of the therapeutic target. Traditional drug discovery is geared towards selecting...