Precision multidimensional assay for high-throughput microRNA drug discovery

Nat Commun. 2016 Feb 16;7:10709. doi: 10.1038/ncomms10709.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • Computer Simulation
  • Drug Discovery / methods*
  • Drug Screening Assays, Antitumor / methods
  • Escherichia coli
  • Flow Cytometry
  • Gene Library
  • High-Throughput Screening Assays / methods*
  • Humans
  • MicroRNAs / drug effects*
  • Microscopy, Fluorescence
  • Molecular Targeted Therapy
  • Small Molecule Libraries

Substances

  • Antineoplastic Agents
  • MicroRNAs
  • Small Molecule Libraries