Expression data from myeloma cell lines treated with 500 nM pristimerin or DMSO vehicle alone for 4 hours. Homo sapiens

As multiple myeloma tumors universally dysregulate cyclin D genes we conducted high-throughput chemical library screens for compounds that induce suppression of cyclin D2. The top-ranked compound was a natural triterpenoid, pristimerin. We used gene expression microarray studies to identify co-regulated pristimerin-response genes and to deduce the compound’s direct molecular target(s), utilizing pattern-matching algorithms available at the Connectivity Map (Cmap). The early transcriptional response of cells treated with pristimerin closely resembles cellular responses elicited by proteosome inhibitors, with rapid induction of heat shock proteins, activating transcription factor (ATF) 3 and CHOP. Enzymatic assays and immunoblotting confirm that pristimerin rapidly (1.5 fold change, FDR<0.25) and the Venn intersection of probe-sets modulated by drug in both cell lines was used in deriving a pristimerin signature.