Anti-chemokine small molecule drugs: a promising future?
BACKGROUND
Chemokines have principally been associated with inflammation due to their role in the control of leukocyte migration, but just over a decade ago chemokine receptors were also identified as playing a pivotal role in the entry of the HIV virus into cells. Chemokines activate seven transmembrane G protein-coupled receptors, making them extremely attractive therapeutic targets for the pharmaceutical industry.


METHODS
Although there are now a large number of molecules targeting chemokines and chemokine receptors including neutralizing antibodies in clinical trials for inflammatory diseases, the results to date have not always been positive, which has been disappointing for the field. These failures have often been attributed to redundancy in the chemokine system. However, other difficulties have been encountered in drug discovery processes targeting the chemokine system, and these will be addressed in this review.


RESULTS
In this review, the reader will get an insight into the hurdles that have to be overcome, learn about some of the pitfalls that may explain the lack of success, and get a glimpse of the outlook for the future.


CONCLUSIONS
In 2007, the FDA approved maraviroc, an inhibitor of CCR5 for the prevention of HIV infection, the first triumph for a small-molecule drug acting on the chemokine system. The time to market, 11 years from discovery of CCR5, was fast by industry standards. A second small-molecule drug, a CXCR4 antagonist for hematopoietic stem cell mobilization, was approved by the FDA at the end of 2008. The results of a Phase III trial with a CCR9 inhibitor for Crohn's disease are also promising. This could herald the first success for a chemokine receptor antagonist as an anti-inflammatory therapeutic and confirms the importance of chemokine receptors as a target class for anti-inflammatory and autoimmune diseases.
Proudfoot
Amanda E I
AE
Merck Serono Geneva Research Center, Merck Serono International SA, 9 Chemin des Mines, 1202 Geneva, Switzerland. amanda.proudfoot@merckserono.net
Power
Christine A
CA
Schwarz
Matthias K
MK
D000818:Animals; D019380:Anti-HIV Agents / Q000494:pharmacology; D018925:Chemokines / Q000037:antagonists & inhibitors*; D002986:Clinical Trials as Topic; D004195:Disease Models, Animal; D016503:Drug Delivery Systems; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology; D006801:Humans; D013045:Species Specificity
D019380:Anti-HIV Agents; D018925:Chemokines