title: Toward performance-diverse small-molecule libraries for cell-based phenotypic screening using multiplexed high-dimensional profiling.
abstract: High-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.
authors.affiliation: Center for the Science of Therapeutics.
authors.forename: Mathias J
authors.initials: MJ
authors.lastname: Wawer
authors.affiliation: Center for the Science of Therapeutics.
authors.forename: Kejie
authors.initials: K
authors.lastname: Li
authors.affiliation: Center for the Science of Therapeutics.
authors.forename: Sigrun M
authors.initials: SM
authors.lastname: Gustafsdottir
authors.affiliation: Imaging Platform.
authors.forename: Vebjorn
authors.initials: V
authors.lastname: Ljosa
authors.affiliation: Center for the Science of Therapeutics.
authors.forename: Nicole E
authors.initials: NE
authors.lastname: Bodycombe
authors.affiliation: Genomics Platform.
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Marton
authors.affiliation: Imaging Platform.
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Sokolnicki
authors.affiliation: Imaging Platform.
authors.forename: Mark-Anthony
authors.initials: MA
authors.lastname: Bray
authors.affiliation: Center for the Science of Therapeutics.
authors.forename: Melissa M
authors.initials: MM
authors.lastname: Kemp
authors.affiliation: Genomics Platform.
authors.forename: Ellen
authors.initials: E
authors.lastname: Winchester
authors.affiliation: Genomics Platform.
authors.forename: Bradley
authors.initials: B
authors.lastname: Taylor
authors.affiliation: Genomics Platform.
authors.forename: George B
authors.initials: GB
authors.lastname: Grant
authors.affiliation: Center for the Science of Therapeutics.
authors.forename: C Suk-Yee
authors.initials: CS
authors.lastname: Hon
authors.affiliation: Center for the Development of Therapeutics, and.
authors.forename: Jeremy R
authors.initials: JR
authors.lastname: Duvall
authors.affiliation: Center for the Science of Therapeutics.
authors.forename: J Anthony
authors.initials: JA
authors.lastname: Wilson
authors.affiliation: Center for the Development of Therapeutics, and.
authors.forename: Joshua A
authors.initials: JA
authors.lastname: Bittker
authors.affiliation: Center for the Science of Therapeutics,Mathematical Institute of the Slovak Academy of Sciences, 04001 Košice, Slovak Republic.
authors.forename: Vlado
authors.initials: V
authors.lastname: Dančík
authors.affiliation: Cancer Program, Broad Institute, Cambridge, MA 02142; and.
authors.forename: Rajiv
authors.initials: R
authors.lastname: Narayan
authors.affiliation: Cancer Program, Broad Institute, Cambridge, MA 02142; and.
authors.forename: Aravind
authors.initials: A
authors.lastname: Subramanian
authors.affiliation: Genomics Platform.
authors.forename: Wendy
authors.initials: W
authors.lastname: Winckler
authors.affiliation: Cancer Program, Broad Institute, Cambridge, MA 02142; and.
authors.forename: Todd R
authors.initials: TR
authors.lastname: Golub
authors.affiliation: Imaging Platform.
authors.forename: Anne E
authors.initials: AE
authors.lastname: Carpenter
authors.affiliation: Center for the Science of Therapeutics.
authors.forename: Alykhan F
authors.initials: AF
authors.lastname: Shamji
authors.affiliation: Center for the Science of Therapeutics, stuart_schreiber@harvard.edu pclemons@broadinstitute.org.
authors.forename: Stuart L
authors.initials: SL
authors.lastname: Schreiber
authors.affiliation: Center for the Science of Therapeutics, stuart_schreiber@harvard.edu pclemons@broadinstitute.org.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Clemons
mesh_terms: D045744:Cell Line, Tumor; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans
keywords: biological activity; biological performance diversity; chemical diversity; chemical similarity