Phenotypic screening in the 21st century.

Abstract

Since the advent of molecular cloning, target based screening has become the norm in pharmaceutical drug discovery. A large number of potential drug targets have been cloned and functionally expressed, and enormous progress has been made in the development, miniaturization and automation of cell based assays on target molecules recombinantly expressed in mammalian cell lines. This approach has delivered many clinical candidates but relatively few new drugs. Target based screening is likely to provide very good drug candidates for monogenic diseases, and the following collection of manuscripts is not meant to discourage the use of target based approaches. However, most of the more prevalent human diseases are most likely multifactorial and require interaction with multiple targets to produce clinically meaningful efficacy. In addition, high potency, selective interaction with a single target may increases the risk of adverse events or be limited by redundancies and adaptive resistance. Here, target agnostic approaches using phenotypic assays may offer significant benefit. Making such approaches viable requires addressing a number of challenges. This e-book attempts to discuss some of these challenges and illustrate recent advances.