A Modern Approach in Drug Discovery: Enabling both Target-based and Phenotypic Assays

摘要

The pursuit of the human genome project in the 1990s led to an explosion of genomic data and putative drug targets based on sequence homology to targets of known drugs. This led drug discovery efforts to adopt almost exclusively a hypothesis-driven, target-based approach, largely at the expense of classical pharmacology approaches that relied on functional (phenotypic) assays linked to the disease, with no a priori knowledge of the mechanism of action [1]. The target-based approach vastly simplified assay development for screening purposes relative to classical pharmacology due to the ability to purify or create recombinant drug targets, which enabled rapid compound screening for binding activity. This resulted in the development of automated, industrialized methods that enabled rapid screening of enormous libraries of small molecule compounds, often in excess of millions of chemical compounds [2]. However, industrialization of high throughput screening did not resolve Pharma's poor R&D productivity issues when seeking new drugs [3]. Many drug candidates emerging from target-based screening efforts failed in clinical trials, often due to efficacy issues. In fact, Phase II clinical trial failures over the period of 2008-2010 were dominated by efficacy problems [4]. This particular attrition was largely due to poor drug target identification and validation studies performed in advance of target-based screening such that the putative drug target was poorly linked to disease modulation.