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Science 303 (5665): 1795-

Copyright © 2004 by the American Association for the Advancement of Science

Rethinking Drug Discovery

Phil Szuromi, Valda Vinson, and Eliot Marshall

Contents
News
Surviving the Blockbuster Syndrome
Orphan Drugs of the Future?
Reviews and Viewpoints
Protein Kinase Inhibitors: Insights into Drug Design from Structure
M. E. M. Noble et al.
Polyketide and Nonribosomal Peptide Antiobiotics: Modularity and Versatility
C. T. Walsh
Organic Chemistry in Drug Discovery
M. MacCoss and T. A. Baillie
The Many Roles of Computation in Drug Discovery
W. L. Jorgensen
Drug Delivery Systems: Entering the Mainstream
T. M. Allen and P. R. Cullis
Related STKE, SAGE KE, and Next Wave material; and Editorial
When we last presented a special issue on Drug Discovery (17 March 2000), our focus was mainly on the deluge of information that genomics, proteomics, combinatorial synthesis, and rapid analytical methods would provide. That information revolution is in full swing, but data alone are not enough. In recent years, the number of new drugs approved annually by the U.S. Food and Drug Administration has at best stayed steady, despite large increases in R&D investment. Industry analysts, meanwhile, have expressed concern over a growing dependence on billion-dollar blockbusters, as Service reports (p. 1796). Has the blockbuster syndrome itself become an obstacle to progress? Or are we simply seeing the normal lag that comes before newly introduced methods bear fruit?

Research, at least, continues to suggest ways out of the doldrums. Walsh (p. 1805) focuses on the modular protein machinery that constructs polyketide and nonribosomal peptide antibiotics. Genetic engineering of the machinery might result in novel antibiotics, and at Science's STKE (www.sciencemag.org/sciext/drugdisc), Shen describes how a synthetic pathway can be engineered in bacteria. Noble et al. (p. 1800) discuss the contribution of structural genomics to drug design for the protein kinase family, and at STKE, Kaelin discusses whether such single-target approaches are likely to be effective against genetically complex cancers. Also at STKE, Philips describes anticancer therapies that target enzymes that process Ras rather than the oncoprotein itself. Charney and Manji discuss how an increased understanding of the underlying pathways could lead to novel potential therapies for treating depression.

MacCoss and Baillie (p. 1810) outline how the synthesis of more effective analogs of lead compounds now takes many cues from the more readily obtained data on bioavailability and toxicity. Jorgensen (p. 1813) reviews how computational methods address these concerns as well as guide the design and screening of compounds for binding to potential biomolecule targets. Allen and Cullis (p. 1818) review how drug delivery systems can improve targeting and reduce toxicity, especially for anticancer and antifungal agents.

At SAGE KE (www.sciencemag.org/sciext/drugdisc), Raber describes the role of isoform-dependent interactions of apoE with androgens and androgen receptors in the progression of Alzheimer's disease. Gibson discusses the state of antioxidant drug discovery in the context of aging and neurodegenerative diseases.

What is clear is that the "pipeline" problem is not caused by a lack of research effort or even funding; Science's Next Wave (www.sciencemag.org/sciext/drugdisc) explores the career potentials and pitfalls of drug discovery. Overcoming the obstacles in drug discovery will likely require continued efforts to provide insights into disease pathways and greater diversity of candidate drug molecules.



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