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

Denis Drygin1, Amy Lin, Josh Bliesath

  • 1Cylene Pharmaceuticals, Inc., San Diego, California, USA.

Cancer Research
|December 17, 2010
PubMed

Insights

CX-5461, a novel small-molecule inhibitor, effectively blocks ribosomal RNA synthesis in cancer cells. This targeted approach shows promise for a new oral cancer therapy by inhibiting RNA polymerase I.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Deregulated ribosomal RNA (rRNA) synthesis is a hallmark of uncontrolled cancer cell proliferation.
  • RNA polymerase I (Pol I) is frequently activated in various cancers, making it a potential therapeutic target.

Purpose of the Study:

  • To design and evaluate CX-5461, a selective small-molecule inhibitor of Pol I, as a potential anti-cancer therapeutic agent.
  • To investigate the mechanism of action and in vivo efficacy of CX-5461 in solid tumor models.

Main Methods:

  • Medicinal chemistry and high-throughput screening were employed to discover CX-5461.
  • Cell-based and molecular assays were used to assess selectivity and mechanism of action.
  • In vivo efficacy was evaluated in murine xenograft models of human solid tumors.

Main Results:

  • CX-5461 selectively inhibits Pol I-driven rRNA synthesis over Pol II transcription, DNA replication, and protein translation.
  • CX-5461 inhibits the initiation of rRNA synthesis, inducing p53-independent senescence and autophagy in solid tumor cells.
  • CX-5461 demonstrated significant in vivo antitumor activity against human solid tumors and is orally bioavailable.

Conclusions:

  • CX-5461 is a potent and selective inhibitor of rRNA synthesis with potential as an orally administered cancer therapeutic.
  • The findings support the advancement of CX-5461 into investigational clinical trials for cancer treatment.

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