Abstract
Drug repurposing aims to find novel indications of clinically used or experimental drugs. Because drug data already exist, drug repurposing may save time and cost, and bypass safety concerns. Polypharmacology, one drug with multiple targets, serves as a basis for drug repurposing. Large-scale databases have been accumulated in recent years, and utilization and integration of these databases would be highly helpful for polypharmacology and drug repurposing. The Connectivity Map (CMap) is a database collecting gene-expression profiles of drug-treated human cancer cells, which has been widely used for investigation of polypharmacology and drug repurposing. In this study, we integrated the next-generation L1000-based CMap and an analytic Web tool, the L1000FWD, for systematic analyses of polypharmacology and drug repurposing. Two different types of anti-cancer drugs were used as proof-of-concept examples, including histone deacetylase (HDAC) inhibitors and topoisomerase inhibitors. We identified KM-00927 and BRD-K75081836 as novel HDAC inhibitors and mitomycin C as a topoisomerase IIB inhibitor. Our study provides a prime example of utilization and integration of the freely available public resources for systematic polypharmacology analysis and drug repurposing.
Highlights
IntroductionKnown as drug repositioning, aims to identify novel indication(s) of an approved or experimental drug [1]
Drug repurposing, known as drug repositioning, aims to identify novel indication(s) of an approved or experimental drug [1]
Because Connectivity Map (CMap) is established based on drug transcriptome profiles, we proposed that CMap is a suitable tool for the discovery of novel histone deacetylase (HDAC) inhibitors by comparing the similarity of gene-expression profiling between the established HDAC inhibitors and CMap drugs
Summary
Known as drug repositioning, aims to identify novel indication(s) of an approved or experimental drug [1]. The Connectivity Map (CMap) is a database that collects microarray-based gene-expression profiles from cultured human cancer cell lines treated with various experimentally and clinically used small molecules, and provides a pattern-matching Web-based software to mine these data [3,4]. Because most CMap compounds are the United States Food and Drug Administration (FDA)-approved drugs, this database has become a powerful tool for drug repurposing. The queried drug may be able to treat the same diseases as the original indications of these CMap drugs. CMap drugs can be repurposed for novel indications if the gene-expression signatures of established clinical drugs are queried
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