2. Academic Validation
  3. Targeting RNA polymerase I with an oral small molecule CX-5461 inhibits ribosomal RNA synthesis and solid tumor growth

Targeting RNA polymerase I with an oral small molecule CX-5461 inhibits ribosomal RNA synthesis and solid tumor growth

  • Cancer Res. 2011 Feb 15;71(4):1418-30. doi: 10.1158/0008-5472.CAN-10-1728.
Denis Drygin 1,  Amy Lin,  Josh Bliesath,  Caroline B Ho,  Sean E O'Brien,  Chris Proffitt,  Mayuko Omori,  Mustapha Haddach,  Michael K Schwaebe,  Adam Siddiqui-Jain,  Nicole Streiner,  Jaclyn E Quin,  Elaine Sanij,  Megan J Bywater,  Ross D Hannan,  David Ryckman,  Kenna Anderes,  William G Rice
Affiliations

Affiliation

  • 1 Cylene Pharmaceuticals, Inc., San Diego, California, USA.
PMID: 21159662 DOI: 10.1158/0008-5472.CAN-10-1728
Abstract

Deregulated ribosomal RNA synthesis is associated with uncontrolled Cancer cell proliferation. RNA polymerase (Pol) I, the multiprotein complex that synthesizes rRNA, is activated widely in Cancer. Thus, selective inhibitors of Pol I may offer a general therapeutic strategy to block Cancer cell proliferation. Coupling medicinal chemistry efforts to tandem cell- and molecular-based screening led to the design of CX-5461, a potent small-molecule inhibitor of rRNA synthesis in Cancer cells. CX-5461 selectively inhibits Pol I-driven transcription relative to Pol II-driven transcription, DNA replication, and protein translation. Molecular studies demonstrate that CX-5461 inhibits the initiation stage of rRNA synthesis and induces both senescence and Autophagy, but not Apoptosis, through a p53-independent process in solid tumor cell lines. CX-5461 is orally bioavailable and demonstrates in vivo antitumor activity against human solid tumors in murine xenograft models. Our findings position CX-5461 for investigational clinical trials as a potent, selective, and orally administered agent for Cancer treatment.

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