title: Precision multidimensional assay for high-throughput microRNA drug discovery.
abstract: Development of drug discovery assays that combine high content with throughput is challenging. Information-processing gene networks can address this challenge by integrating multiple potential targets of drug candidates' activities into a small number of informative readouts, reporting simultaneously on specific and non-specific effects. Here we show a family of networks implementing this concept in a cell-based drug discovery assay for miRNA drug targets. The networks comprise multiple modules reporting on specific effects towards an intended miRNA target, together with non-specific effects on gene expression, off-target miRNAs and RNA interference pathway. We validate the assays using known perturbations of on- and off-target miRNAs, and evaluate an ∼700 compound library in an automated screen with a follow-up on specific and non-specific hits. We further customize and validate assays for additional drug targets and non-specific inputs. Our study offers a novel framework for precision drug discovery assays applicable to diverse target families.
authors.affiliation: Department of Biosystems Science and Engineering, Swiss Federal Institute of Technology (ETH Zürich), Mattenstrasse 26, 4058 Basel, Switzerland.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Haefliger
authors.affiliation: Department of Biosystems Science and Engineering, Swiss Federal Institute of Technology (ETH Zürich), Mattenstrasse 26, 4058 Basel, Switzerland.
authors.forename: Laura
authors.initials: L
authors.lastname: Prochazka
authors.affiliation: Department of Biosystems Science and Engineering, Swiss Federal Institute of Technology (ETH Zürich), Mattenstrasse 26, 4058 Basel, Switzerland.
authors.forename: Bartolomeo
authors.initials: B
authors.lastname: Angelici
authors.affiliation: Department of Biosystems Science and Engineering, Swiss Federal Institute of Technology (ETH Zürich), Mattenstrasse 26, 4058 Basel, Switzerland.
authors.forename: Yaakov
authors.initials: Y
authors.lastname: Benenson
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003198:Computer Simulation; D055808:Drug Discovery / Q000379:methods*; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D004926:Escherichia coli; D005434:Flow Cytometry; D015723:Gene Library; D057166:High-Throughput Screening Assays / Q000379:methods*; D006801:Humans; D035683:MicroRNAs / Q000187:drug effects*; D008856:Microscopy, Fluorescence; D058990:Molecular Targeted Therapy; D054852:Small Molecule Libraries
chemical_list: D000970:Antineoplastic Agents; D035683:MicroRNAs; D054852:Small Molecule Libraries