Drug Discovery

Figure 1. The drug discovery pipeline, emphasizing gross progress through research and human clinical trials and ultimately FDA registration and approval. From Allen D. Roses, Nature Rev Drug Disc. 7, 807-817 (2008).

Drugs are molecules that modulate protein receptors in human cells or pathogens, treating a disease. They are notoriously difficult to discover and develop, and recent industrial estimates suggest that the cost of bringing a drug to market is about four billion dollars. While there is reason to question this estimate, there is no doubt that developing a new therapeutic is hugely expensive, requiring a vertically integrated research enterprise. It often begins with the discovery of a new receptor in the cell, proceeds to the discovery of molecules that can modulate that receptor, continues to the optimization of those molecules for activity in ever more complex animal models, for specificity, lack of toxicity, stability, and dosage form. Only when shown to be effective and safe in representative animal models are the molecules advanced into human clinical trials, which can demand testing in tens of thousands of patients over several years (Figure 1).

Because of the high cost and great risks of drug discovery, basic research only occasionally leads directly to a drug, (though there are important examples where it has), but it makes crucial contributions at almost every point of the drug discovery pipeline (Figure 1) Nowhere is this truer than at QBI UCSF, where the modern molecular era of drug discovery was partly invented. UCSF investigators are developing technologies for discovering new drug targets, understanding their mechanism of action, and finding new molecules that modulate them. Methods to discover these early drug candidates include molecular design, computer-based drug discovery, empirical and phenotypic screening, and by protein engineering. For several of these, the field depends on technologies, databases and libraries that were developed and are hosted by the university. The development of CRISPR technologies has enabled the design of elegant animal models to test the mechanisms of these drugs, and to understand their off-target liabilities. UCSF investigators are also developing new methods to predict and understand how drugs permeate membranes and barriers in the body, and the effects of the excipients that are co-formulated with drugs, and often make up most of the weight of pills.