PMID- 23936032
OWN - NLM
STAT- MEDLINE
DCOM- 20140305
LR  - 20211021
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 8
IP  - 7
DP  - 2013
TI  - Integrated analysis of drug-induced gene expression profiles predicts novel hERG 
      inhibitors.
PG  - e69513
LID - 10.1371/journal.pone.0069513 [doi]
LID - e69513
AB  - Growing evidence suggests that drugs interact with diverse molecular targets 
      mediating both therapeutic and toxic effects. Prediction of these complex 
      interactions from chemical structures alone remains challenging, as compounds 
      with different structures may possess similar toxicity profiles. In contrast, 
      predictions based on systems-level measurements of drug effect may reveal 
      pharmacologic similarities not evident from structure or known therapeutic 
      indications. Here we utilized drug-induced transcriptional responses in the 
      Connectivity Map (CMap) to discover such similarities among diverse antagonists 
      of the human ether-a-go-go related (hERG) potassium channel, a common target of 
      promiscuous inhibition by small molecules. Analysis of transcriptional profiles 
      generated in three independent cell lines revealed clusters enriched for hERG 
      inhibitors annotated using a database of experimental measurements (hERGcentral) 
      and clinical indications. As a validation, we experimentally identified novel 
      hERG inhibitors among the unannotated drugs in these enriched clusters, 
      suggesting transcriptional responses may serve as predictive surrogates of 
      cardiotoxicity complementing existing functional assays.
FAU - Babcock, Joseph J
AU  - Babcock JJ
AD  - The Solomon H. Snyder Department of Neuroscience and High Throughput Biology 
      Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, 
      United States of America.
FAU - Du, Fang
AU  - Du F
FAU - Xu, Kaiping
AU  - Xu K
FAU - Wheelan, Sarah J
AU  - Wheelan SJ
FAU - Li, Min
AU  - Li M
LA  - eng
GR  - R01 GM078579/GM/NIGMS NIH HHS/United States
GR  - U54 MH084691/MH/NIMH NIH HHS/United States
GR  - GM078579/GM/NIGMS NIH HHS/United States
GR  - MH084691/MH/NIMH NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20130723
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Ether-A-Go-Go Potassium Channels)
RN  - 0 (Pharmaceutical Preparations)
RN  - 0 (Potassium Channel Blockers)
SB  - IM
MH  - Cluster Analysis
MH  - Ether-A-Go-Go Potassium Channels/*antagonists & inhibitors/metabolism
MH  - *Gene Expression Profiling
MH  - Gene Regulatory Networks/genetics
MH  - Humans
MH  - Oligonucleotide Array Sequence Analysis
MH  - Pharmaceutical Preparations/*metabolism
MH  - Potassium Channel Blockers/*pharmacology
MH  - Reproducibility of Results
MH  - Transcription, Genetic/drug effects
PMC - PMC3720659
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2013/08/13 06:00
MHDA- 2014/03/07 06:00
PMCR- 2013/07/23
CRDT- 2013/08/13 06:00
PHST- 2013/01/18 00:00 [received]
PHST- 2013/06/07 00:00 [accepted]
PHST- 2013/08/13 06:00 [entrez]
PHST- 2013/08/13 06:00 [pubmed]
PHST- 2014/03/07 06:00 [medline]
PHST- 2013/07/23 00:00 [pmc-release]
AID - PONE-D-13-03089 [pii]
AID - 10.1371/journal.pone.0069513 [doi]
PST - epublish
SO  - PLoS One. 2013 Jul 23;8(7):e69513. doi: 10.1371/journal.pone.0069513. Print 2013.