The very best validated targets have been identified as the result of extensive studies of the biology of disease pathways, usually over years and even decades, by academic and biotechnology company researchers. The targets for the majority of breakthrough drugs that have reached the market in recent years were identified via such research.
In contrast, not one marketed drug has so far resulted from large-scale target identification and validation testing. This disparity is reflected in the statement in a recent article by Mark Fishman and Jeffrey Porter of Novartis that target validation does not take one year (as usually shown in drug development timelines) but decades.1
If drug discovery researchers can utilize a target derived from basic biological and medical research, this eliminates the need to sort through hundreds or thousands of targets using target identification and validation technologies. However, many, and perhaps the majority of such well-validated targets, are not deemed to be druggable. Some pathways contain no druggable elements.
For example, the central, or intrinsic pathway of apoptosis is typically blocked in cancer cells. Many companies would like to develop drugs that overcome these blocks and thus induce programmed cell death in the cancer cells. However, all of the potential targets in the intrinsic pathway of apoptosis are undruggable protein-protein interactions. As a result, the majority of pro-apoptotic agents in clinical trials are antisense compounds.
Given the drug delivery and other issues with antisense drugs, companies would prefer to develop small molecule compounds. In this and many other cases, expanding the universe of druggable targets would allow drug discovery researchers to access well-validated targets rather than attempting to utilize targets of largely unknown value.
A pragmatic definition of druggability is that researchers have the appropriate science and technology in hand to develop antagonists to a particular target. In the case of small molecule drugs, druggable targets are those that can be addressed with currently available medicinal chemistry. These targets especially include those belonging to protein families that are targeted with currently marketed drugsspecifically G-protein coupled receptors, ion channels, nuclear receptors, proteases, phosphodiesterases, kinases, and other key enzymes.
Druggable targets for large molecule drugs are the secreted proteins, both those expressed on the cell membrane and those secreted into extracellular fluids, especially blood plasma. Cell surface receptors are targets for development of monoclonal antibodies (Mabs) and recombinant fusion proteins that carry protein ligands for the receptors.
Recombinant versions of extracellularly secreted proteins may be used as therapeutic proteins such as erythropoietin (Amgen's Epogen and Aranesp), granulocyte colony-stimulating factor (Amgen's filgastrim and pegfilgastrim), and interferons (Berlex' betaseron [interferon beta-1b] and Biogen Idec's Avonex [interferon beta-1a]).
Medicinal chemists have a useful body of science and experience that predicts druggability of targets as well as drug-like properties of small molecule compounds that may interact with these targets.
However, what constitutes druggability has undergone expansion in recent years. For example, protein kinases were traditionally considered undruggable. However, there are now several protein kinase inhibitors on the market and many more in development, and nearly all big pharmas and many biotechnology companies have kinase discovery and development programs.
Protein phosphatases present greater difficulties to medical chemists because their natural substrates are highly charged; mimetics of such polar substrates will be expected to have difficulty entering into cells. However, such companies as Pfizer, Roche, Abbott, and Incyte, as well as academic groups, are making apparent headway in exploring novel approaches to discovery of phosphatase inhibitors.