Meeting Highlights 2004 © Ashley Publications Ltd ISSN 1354-3784 1213 Ashley Publications ww w.ashley-pub.com 1. Meeting highlights 2. Expert opinion New Advances in Drug Discovery Keystone, Colorado, USA, March 21 – 26, 2004 Colin Macphee Department of Vascular Biology and Thrombosis, GlaxoSmithKline, King of Prussia, PA, USA The conference covered the most exciting recent advances in industry and academia in areas related to drug discovery and development. Topics included candidates currently in clinical development, new technologies aimed at facilitating the drug discovery process and potential new targets. Targets in clinical development included inhibitors of lipoprotein-associated phospholipase A 2 for atherosclerosis, IL-1β converting enzyme inhibitors for inflammatory disorders and a novel proteasome inhibitor for cancer therapy. New technologies covered a novel system for screening ion channel function, various applications for RNA interference, different imaging modalities, as well as mRNA microarrays to facilitate toxicological assessment. New targets included the ATP-binding cassette family of transporters and the recently elu- cidated sulfation pathways. Keywords: Alzheimer's disease, atherosclerosis, drug discovery, G-protein coupled receptors, imaging, inflammation, microarrays, myeloma, new targets, RNA interference Expert Opin. Investig. Drugs (2004) 13(9):1213-1215 1. Meeting highlights T he conference opened with an overview of the evidence supporting the role of the secreted enzyme lipoprotein-associated phospholipase A 2 (Lp-PLA 2 ) in promoting atherosclerosis in humans (C Macphee, GlaxoSmithKline, PA, USA). Novel, potent and highly selective inhibitors have been identified that have been used to confirm a role in atherogenesis. T he hypothesis, in this instance, is based upon the knowledge that Lp-PLA 2 is capable of generating two proven pro-atherogenic lipid mediators, lyso-phosphatidylcholine and oxidised free fatty acids. In addition, various epidemiological studies have demonstrated elevated Lp-PLA 2 levels as an independ- ent risk marker of disease in primary and secondary prevention patient populations. An inhibitor, SB-480848, is currently in Phase II clinical trials. IL-1β converting enzyme (ICE) processes inactive cytokine precursors to biolog- ically active forms and, as such, is a target for the treatment of inflammatory and autoimmune diseases. J Randle (Vertex, MA, USA) described clinical data obtained with the first selective ICE inhibitor, pralnacasan (VX-740). In a Phase IIa trial in rheumatoid arthritis, pralnacasan, in addition to inhibiting IL-1β production in an ex vivo whole blood assay, produced dose-dependent reductions in various serum markers of inflammation, including C-reactive protein. In addition, this novel ICE inhibitor allowed for a dose-dependent reduction in the use of oral corticosteroids. The exact therapeutic indication for an ICE inhibitor is still being debated and a second improved ICE inhibitor, VX-765, has recently entered clinical develop- ment. VX-765 50 mg/kg was very effective in an oxazolone-induced dermatitis model where it significantly reduced not only IL-1 β and IL-18 but also the chem- okines monocyte chemoattractant protein-1 (MCP-1) and macrophage inflamma- tory protein-1 α (MIP-1 α29 . T he third clinical candidate discussed was bortezomib (Velcade™ ), which has recently been approved for the treatment of multiple myeloma (J Adams, Infinity Pharmaceuticals, MA, USA). Bortezomib is a novel, first-in-class proteasome inhibitor. Cancer cells appear to be more sensitive to this agent than normal cells. For reprint orders, please contact: reprints@ashley-pub.com