Phenotypic Screening of Drug Library in Actively Differentiating Mouse Embryonic Stem Cells

Phenotypic screening enables the discovery of new drug leads with novel targets. ES cells differentiate into different lineages by successively making use of different subsets of the genome's possible macromolecular interactions. If a compound effectively targets just one of these interactions, it derails the developmental pathway to produce a phenotypical change. The OTRADI microsource spectrum library of 2000 approved drug components, natural products, and bioactive components was screened for compounds that can induce phenotypic changes in ES cell cultures at 10 mu M after 3 days. Twenty-one compounds that induced specific morphologies also induced unique changes to an expression profile of a dozen markers of early embryonic development, indicating that each compound has derailed the molecular developmental process in a characteristic way. Phenotypic screens conducted with ES cultures differentiating along different lineages can be used to efficiently prescreen compounds able to regulate cell differentiation lineage.