RNA polymerase I (
RNA Pol I) is a "factory" that orchestrates the transcription of
ribosomal RNA for constructing ribosomes as a primary workshop for protein translation to sustain cell growth. The deregulation of
RNA Pol I often causes uncontrolled cell proliferation, leading to
cancer. Efficient and reliable methods are needed for the identification of selective inhibitors of
RNA Pol I. Yeast (Saccharomyces cerevisiae) is eukaryotic and represents a valuable model system to study
RNA Pol I, especially with the availability of the X-ray crystal structure of the yeast homologue of
RNA Pol I, offering a structural basis to selectively target this transcriptional machinery. Herein, we developed a cell-based screening strategy by establishing a stable yeast cell line with a stably integrated human
RNA Pol I promoter and
ribosomal DNA. The model system was validated using the well-known
RNA Pol I inhibitor
CX-5461 by measuring transcribed human rRNA as readout. Virtual screening coupled with compound library screening using this cell line enabled the identification of a new candidate inhibitor of
RNA Pol I, namely,
cerivastatin sodium. Furthermore, we used growth and transcription activity assays to biologically evaluate the hit compound. Preliminary studies demonstrated antiproliferative effects of
cerivastatin sodium against human
cancer cells, namely, A2780 and H460 cell lines. These results implicated
cerivastatin sodium as a selective
RNA Pol I inhibitor worthy of further development together with potential as a targeted anticancer therapeutic.