The majority of current drug discovery strategies are directed towards specific, molecular targets. However, analysis of FDA approved drugs indicates that the majority of first in class new molecular entities (NMEs) originated from phenotypic and not target-directed screening. Phenotypic drug discovery (PDD) approaches are not commonly used by Pharma due to concerns about assay performance, difficulties with compound structure-activity relationships (SAR), uncertain applicability of chemo-informatics, and the difficulty/requirement for elucidating a molecular target. We address these perceived issues with PDD by conducting a medium through-put screen using a co-culture angiogenesis assay. Results indicate that modern phenotypic assays can reliably provide information on compound SAR. Identification of compounds which modulate targets not previously associated with angiogenesis demonstrates that PDD directly interrogates relevant biology without preconceptions of target validation state. These attributes of PDD enabled the identification of compounds which are structurally and mechanistically distinct from current standard of care (SOC) and are active in vivo.
The potential synergism between novel chemical diversity and the target agnostic PDD approach was investigated by comparing the phenotypic assay profiles of compounds derived from Pharma verses structurally distinct molecules from academia/biotech. Taken together our results indicate that modern PDD combines advantages of pharmacology based drug discovery with the high through-put compound testing capacity and operational robustness of targeted approaches. Novel chemical diversity coupled with phenotypic lead generation strategies will facilitate the identification of novel therapeutic mechanisms and the validation of new molecular targets.