2. Academic Validation
  3. A targeting modality for destruction of RNA polymerase I that possesses anticancer activity

A targeting modality for destruction of RNA polymerase I that possesses anticancer activity

  • Cancer Cell. 2014 Jan 13;25(1):77-90. doi: 10.1016/j.ccr.2013.12.009.
Karita Peltonen 1,  Laureen Colis 2,  Hester Liu 2,  Rishi Trivedi 2,  Michael S Moubarek 3,  Henna M Moore 1,  Baoyan Bai 2,  Michelle A Rudek 4,  Charles J Bieberich 3,  Marikki Laiho 5
Affiliations

Affiliations

  • 1 Molecular Cancer Biology Program and Centre for Drug Research, University of Helsinki, Helsinki 00014, Finland.
  • 2 Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
  • 3 Department of Biological Sciences, University of Maryland Baltimore County, Baltimore, MD 21250, USA.
  • 4 Department of Oncology and The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
  • 5 Molecular Cancer Biology Program and Centre for Drug Research, University of Helsinki, Helsinki 00014, Finland; Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; Department of Oncology and The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA. Electronic address: mlaiho1@jhmi.edu.
PMID: 24434211 DOI: 10.1016/j.ccr.2013.12.009
Abstract

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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-12484
    99.25%, DNA Intercalator/Pol I Elongation Inhibitor