In modern drug discovery, high-throughput screening has become a fundamental methodology for identifying novel small-molecule probes and drug leads.[1] However, the question of how to design efficient compound collections for biochemical and phenotypic screening is unresolved. Recently, the medicinal chemistry community has become increasingly aware of the value of utilizing compound collections containing structurally diverse molecules with a high three-dimensionality for the identification of new therapeutic leads. Despite this, most of the currently available corporate compound collections are comprised primarily of flat, sp2-rich molecules that have limited opportunities to interact with challenging biological targets, such as DNA-protein interactions, transcription factors and protein-protein interactions.[2] To facilitate the creation of compound libraries with high chemical diversity and high three-dimensional content suitable for use in phenotypic screening, our group has developed a cell-painting assay, which allows a rapid multiplex cytological profiling of compounds based on their effects on over 800 cell morphology features. This assay allows a preselection of compounds that exhibit biological activity, and can be further used to compare compounds by their cell morphology profiles to identify known or novel cellular mechanisms of action. This rapid feedback to synthetic chemists facilitates a subsequent prioritization of chemical reactions and compounds in terms of their biologically performance.[3] In this study, a series of chiral complex molecules assembled by the use of photoredox catalysis and intramolecular Diels-Alder chemistry have been evaluated for their effects on the human osteosarcoma U2OS cell line using the cell-painting assay. Here, we identified several compounds with distinctive cellular mechanisms of action and compared those to over 20,000 compounds from the diversity-oriented synthesis library at the Broad Institute and over 12,000 known bioactive compounds. References: [1] R. Macarron, et al., Nat. Rev. Drug Discov. 2011, 10, 188–195. [2] T. E. Nielsen, S. L. Schreiber, Angew. Chem. Int. Ed. 2008, 47, 48–56. [3] a) M. J. Wawer, et al., Proc. Natl. Acad. Sci. U.S.A, 2014, 111, 10911-10916; b) S. M. Gustafsdottir, et al., PLoS One 2013, 8, 12, e80999; c) M. J. Wawer, et al., J. Biomol. Screen. 2014, 19, 738–748.

Novel biologically performance-diverse compounds

251st National Meeting (2016)

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