A Targeting Modality for Destruction of RNA Polymerase I that Possesses Anticancer Activity
Menée in vitro et in vivo, cette étude évalue l'activité antitumorale et les mécanismes d'action d'un composé appelé BMH-21
We 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. "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