What is the druggable genome?

The importance of drug discovery is reflected in its long history, starting thousands of years ago with natural remedies and leading to the estimated $825 billion annual global pharmaceutical market that exists today. Thus, the definition of the druggable genome, or defining those molecular entities within the human genome that can be manipulated to improve health, impacts the direction of drug discovery research around the globe. New advances in genomics studies and modern medicine have transformed both the process of drug discovery and the definition of the druggable genome. Historically, the drug discovery process used a “forward pharmacology” approach whereby an active compound was identified based on its efficacy, and then its mechanism of action was determined. This approach was limited by the availability of appropriate animal models but had the advantage of identification of drugs with efficacy in vivo. As understanding of the molecular basis of cellular function has increased, the drug discovery process has moved toward a “reverse pharmacology” approach, whereby drug targets are defined and then compounds affecting their function are identified.

The shift in focus of drug discovery into the reverse pharmacology approach has led to the development of a whole field of “biologicals,” biologically created products as opposed to chemically synthesized products, for targeting proteins. For example, numerous therapeutic monoclonal antibodies have been successfully developed, including Enbrel, a monoclonal antibody that functions as a tumor necrosis factor antagonist and has proven successful for the treatment of rheumatoid arthritis (for review, see Silva et al. [1]) and Herceptin, a monoclonal antibody that interferes with the HER2/neu receptor and is used as an adjuvant treatment in patients with HER2-overexpressing breast cancer (for review of cancer immunotherapy and Herceptin, see Dillman [2]). Although biologicals have received increasing attention because of recent successes, they are limited by the restricted properties of target proteins, poor oral availability, and high cost of manufacture. As a result, the identification of therapeutic small molecules has remained the main focus of drug discovery.