A Targeting Modality for Destruction of RNA Polymerase I that Possesses Anticancer Activity

• Small molecule compound BMH-21 potently decreases the viability of cancer cells
• BMH-21 binds ribosomal DNA and inhibits Pol I transcription
• BMH-21 leads to proteasome-dependent destruction of Pol I catalytic subunit RPA194
• BMH-21 represents a viable class of cancer therapeutic molecules

SummaryWe define the activity and mechanisms of action of a small molecule lead compound for cancer targeting. We show that the compound, BMH-21, has wide and potent antitumorigenic activity across NCI60 cancer cell lines and represses tumor growth in vivo. BMH-21 binds GC-rich sequences, which are present at a high frequency in ribosomal DNA genes, and potently and rapidly represses RNA polymerase I (Pol I) transcription. Strikingly, we find that BMH-21 causes proteasome-dependent destruction of RPA194, the large catalytic subunit protein of Pol I holocomplex, and this correlates with cancer cell killing. Our results show that Pol I activity is under proteasome-mediated control, which reveals an unexpected therapeutic opportunity.

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