title: Evidence-Based and Quantitative Prioritization of Tool Compounds in Phenotypic Drug Discovery.
abstract: The use of potent and selective chemical tools with well-defined targets can help elucidate biological processes driving phenotypes in phenotypic screens. However, identification of selective compounds en masse to create targeted screening sets is non-trivial. A systematic approach is needed to prioritize probes, which prevents the repeated use of published but unselective compounds. Here we performed a meta-analysis of integrated large-scale, heterogeneous bioactivity data to create an evidence-based, quantitative metric to systematically rank tool compounds for targets. Our tool score (TS) was then tested on hundreds of compounds by assessing their activity profiles in a panel of 41 cell-based pathway assays. We demonstrate that high-TS tools show more reliably selective phenotypic profiles than lower-TS compounds. Additionally we highlight frequently tested compounds that are non-selective tools and distinguish target family polypharmacology from cross-family promiscuity. TS can therefore be used to prioritize compounds from heterogeneous databases for phenotypic screening.
authors.affiliation: Novartis Institutes for BioMedical Research Inc., 250 Massachusetts Avenue, Cambridge, MA 02139, USA. Electronic address: yuan-2.wang@novartis.com.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Novartis Institutes for BioMedical Research Inc., 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Allen
authors.initials: A
authors.lastname: Cornett
authors.affiliation: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 92121, USA.
authors.forename: Fred J
authors.initials: FJ
authors.lastname: King
authors.affiliation: Harvard T.H. Chan School of Public Health, 677 Huntington Avenue, Boston, MA 02115, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Mao
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Pharma AG, Novartis Campus, Basel 4056, Switzerland.
authors.forename: Florian
authors.initials: F
authors.lastname: Nigsch
authors.affiliation: Novartis Institutes for BioMedical Research Inc., 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: C Gregory
authors.initials: CG
authors.lastname: Paris
authors.affiliation: Novartis Institutes for BioMedical Research Inc., 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Gregory
authors.initials: G
authors.lastname: McAllister
authors.affiliation: Novartis Institutes for BioMedical Research Inc., 250 Massachusetts Avenue, Cambridge, MA 02139, USA. Electronic address: jeremy.jenkins@novartis.com.
authors.forename: Jeremy L
authors.initials: JL
authors.lastname: Jenkins
mesh_terms: D001331:Automation; D002460:Cell Line; D062126:Databases, Chemical; D055808:Drug Discovery; D057166:High-Throughput Screening Assays; D006801:Humans; D015335:Molecular Probes / Q000737:chemistry*; D015394:Molecular Structure; D010641:Phenotype
chemical_list: D015335:Molecular Probes