Figure 2.

Basic steps in phenotypic drug discovery and development. The basic phenotypic approach involves steps that begin with the biology of the disease. Although a holistic approach to the disease has not usually been applied at this point, additional information has been gleaned from patient data and network analyses as part of basic scientific information. The next steps include the identification (ID), recapitulation, and validation of a disease-relevant phenotype in cell-based and/or organism-based models. The next step involves the development of a phenotypic assay that can be one of two major types: (1) unbiased modulation of a specific pathway identified in the validation step³ or (2) an unbiased modulation of a disease phenotype that may involve any or multiple pathways in which the goal is to modulate the disease phenotype to a more normal phenotype⁴ followed by screening of selected libraries and then the generation of leads from the validated hits.^5,6 The next step involves the optimization of leads and, increasingly, the application of early safety and absorption, distribution, metabolism, and excretion testing in vitro followed by the use of methods such as chemical proteomics and RNAi knockdowns to identify on-target and off-target interactions of the leads. If molecular targets are identified during target ID studies, it is possible to shift to the target-centric approach for structure-activity relationship. The next step involves preclinical testing with animal models followed by phase I to III clinical trials.