Elucidating the modes of action for bioactive compounds in a cell-specific manner by large-scale chemically-induced transcriptomics

Michio Iwata, Ryusuke Sawada, Hiroaki Iwata, Masaaki Kotera, Yoshihiro Yamanishi

Research output: Contribution to journalArticlepeer-review

20 Citations (Scopus)

Abstract

The identification of the modes of action of bioactive compounds is a major challenge in chemical systems biology of diseases. Genome-wide expression profiling of transcriptional responses to compound treatment for human cell lines is a promising unbiased approach for the mode-of-action analysis. Here we developed a novel approach to elucidate the modes of action of bioactive compounds in a cell-specific manner using large-scale chemically-induced transcriptome data acquired from the Library of Integrated Network-based Cellular Signatures (LINCS), and analyzed 16,268 compounds and 68 human cell lines. First, we performed pathway enrichment analyses of regulated genes to reveal active pathways among 163 biological pathways. Next, we explored potential target proteins (including primary targets and off-targets) with cell-specific transcriptional similarity using chemical-protein interactome. Finally, we predicted new therapeutic indications for 461 diseases based on the target proteins. We showed the usefulness of the proposed approach in terms of prediction coverage, interpretation, and large-scale applicability, and validated the new prediction results experimentally by an in vitro cellular assay. The approach has a high potential for advancing drug discovery and repositioning.

Original languageEnglish
Article number40164
JournalScientific reports
Volume7
DOIs
Publication statusPublished - Jan 10 2017

All Science Journal Classification (ASJC) codes

  • General

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