Scientific Publications

Toward performance-diverse small-molecule libraries for cell-based phenotypic screening using multiplexed high-dimensional profiling.

Publication TypeJournal Article
AuthorsWawer, MJ, Li K., Gustafsdottir SM, Ljosa V., Bodycombe NE, Marton MA, Sokolnicki KL, Bray MA, Kemp MM, Winchester E., Taylor B., Grant GB, Hon CS, Duvall JR, Wilson JA, Bittker JA, Dančík V., Narayan R., Subramanian A., Winckler W., Golub T. R., Carpenter AE, Shamji AF, Schreiber SL, and Clemons PA
AbstractHigh-throughput screening has become a mainstay of small-molecule probe and early drug discovery. The question of how to build and evolve efficient screening collections systematically for cell-based and biochemical screening is still unresolved. It is often assumed that chemical structure diversity leads to diverse biological performance of a library. Here, we confirm earlier results showing that this inference is not always valid and suggest instead using biological measurement diversity derived from multiplexed profiling in the construction of libraries with diverse assay performance patterns for cell-based screens. Rather than using results from tens or hundreds of completed assays, which is resource intensive and not easily extensible, we use high-dimensional image-based cell morphology and gene expression profiles. We piloted this approach using over 30,000 compounds. We show that small-molecule profiling can be used to select compound sets with high rates of activity and diverse biological performance.
Year of Publication2014
JournalProceedings of the National Academy of Sciences of the United States of America
Date Published (YYYY/MM/DD)2014/07/14
ISSN Number0027-8424
DOI10.1073/pnas.1410933111
PubMedhttp://www.ncbi.nlm.nih.gov/pubmed/25024206?dopt=Abstract