Integrated Analysis of Drug-Induced Gene Expression Profiles Predicts Novel hERG Inhibitors
Figure 1
Pipeline for construction and analysis of drug transcriptional response network.
Raw microarray data for drugs profiled in three cancer cell lines in the Connectivity Map (left) are normalized and clustered using affinity propagation (top center) based on similarities in drug-induced gene expression profiles (nodes) to yield clusters with a characteristic “exemplar” (highlighted by red) representing the expression profile shared by cluster members. The resulting clusters (middle center) are annotated for experimental and clinical evidence of hERG inhibition (bottom center), and enrichment analysis conducted to find clusters with a statistically significant fraction of hERG inhibitors. Unannotated compounds in these enriched clusters (top right) are then experimentally assessed for hERG inhibition in a high-throughput electrophysiology assay (middle right) to yield potency values (bottom right).