Drug discovery targeting the chemokine system--where are we?
The identification of a large cytokine sub-family responsible for the control of the directional migration of leukocytes over 20 years ago brought much excitement to the pharmaceutical industry with the promise of a new family of targets to treat inflammatory diseases. This family of small proteins, subsequently named chemokines, were identified as acting on seven transmembrane spanning (7TM) G protein-coupled receptors - one of the most druggable classes of receptors in the pharmaceutical industry. The interest in chemokines and their receptors as therapeutic targets subsequently evolved beyond inflammation to include cancer and infectious disease such as AIDS, as chemokine biology progressed to demonstrate their role in these processes. The first inhibitors entered the clinic some 7 years ago. However progress and success has not been as rapid as hoped for: both in the identification of candidate molecules as well as their efficacy in the clinic. We will address the chemokine system as drug targets, issues involved in the development of therapeutic candidates and attempt to address the pitfalls and potential routes to success.
Horuk
Richard
R
UC Davis, Department of Pharmacology, 451 Health Sciences Drive, Davis, CA 95616, USA.
Proudfoot
Amanda E I
AE
D000818:Animals; D057134:Antibodies, Neutralizing / Q000378:metabolism; D018925:Chemokines / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D003141:Communicable Diseases / Q000188:drug therapy*; D015195:Drug Design; D055808:Drug Discovery / Q000379:methods*; D019143:Evolution, Molecular; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy*; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
D057134:Antibodies, Neutralizing; D018925:Chemokines; D019707:Receptors, Chemokine; D043562:Receptors, G-Protein-Coupled