You are here

Proc Natl Acad Sci U S A DOI:10.1073/pnas.1410933111

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

Publication TypeJournal Article
Year of Publication2014
AuthorsWawer, MJ, Li, K, Gustafsdottir, SM, Ljosa, V, Bodycombe, NE, Marton, MA, Sokolnicki, KL, Bray, M-A, Kemp, MM, Winchester, E, Taylor, B, Grant, GB, C Hon, S-Y, Duvall, JR, J Wilson, A, Bittker, JA, Dančík, V, Narayan, R, Subramanian, A, Winckler, W, Golub, TR, Carpenter, AE, Shamji, AF, Schreiber, SL, Clemons, PA
JournalProc Natl Acad Sci U S A
Volume111
Issue30
Pages10911-6
Date Published2014 Jul 29
ISSN1091-6490
KeywordsCell Line, Tumor, Drug Evaluation, Preclinical, Gene Expression Profiling, Gene Expression Regulation, Humans
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.

URLhttp://www.pnas.org/cgi/pmidlookup?view=long&pmid=25024206
DOI10.1073/pnas.1410933111
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/25024206?dopt=Abstract

Alternate JournalProc. Natl. Acad. Sci. U.S.A.
PubMed ID25024206
PubMed Central IDPMC4121832
Grant ListP50-GM069721 / GM / NIGMS NIH HHS / United States
U54 HG005032 / HG / NHGRI NIH HHS / United States
U54 HG006093 / HG / NHGRI NIH HHS / United States
P50 GM069721 / GM / NIGMS NIH HHS / United States
U54HG005032 / HG / NHGRI NIH HHS / United States