The early cellular genetic response to pristimerin closely resembles genomic responses to proteosome and HSP90 inhibitors. (A) Genome-wide expression data from cell lines treated with vehicle or pristimerin 500 nM for 4 hours were used to generate a pristimerin early response gene signature that was then analyzed using Cmap (Build 2) to identify similarities between the pristimerin-induced biologic response and that of other drugs. More than 6000 unique expression profiles from 1309 compounds (some with multiple instances representing distinct cell lines or time points) were compared and rank-ordered for similarity to pristimerin's signature. The gray column represents the dataset of 6000 expression profiles. Four of the top-ranked profiles (red bars at the top of column), resembling the pristimerin signature, were from proteosome inhibitors, MG-132 (1/1 instance) and MG-262 (all 3/3 instances in dataset). Some gene response profiles from HSP90 inhibitors (blue bars: one per database instance) also closely resembled that of pristimerin, although other HSP90 profile instances were less closely matched, possibly reflecting the duration of drug exposure or cell line tested. (B-E) To the right are graphic representations of the connectivity scores for the gene expression signature of pristimerin and proteosome inhibitors (B) MG-132 or (C) MG-262, or Hsp90 inhibitors (D) tanespimycin (17-AAG) and (E) monorden, showing marked enrichment of the pristimerin signature in expression responses for these drugs. Interpretation of the plots and connectivity score is described at http://www.broad.mit.edu/cmap.