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Updated: Apr 28, 2026

A Flow Cytometry-based Assay to Identify Compounds That Disrupt Binding of Fluorescently-labeled CXC Chemokine Ligand 12 to CXC Chemokine Receptor 4
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Discovery of CX-5461, the First Direct and Selective Inhibitor of RNA Polymerase I, for Cancer Therapeutics

Mustapha Haddach1, Michael K Schwaebe1, Jerome Michaux1

  • 1Cylene Pharmaceuticals , 5820 Nancy Ridge Drive, Suite 200, San Diego, California 92121, United States.

ACS Medicinal Chemistry Letters
|June 6, 2014
PubMed

Insights

Cancer cells accelerate rDNA transcription via RNA polymerase I (Pol I) to fuel growth. CX-5461 is the first selective, orally available Pol I inhibitor showing promise as an anticancer therapeutic.

Area of Science:

  • Molecular Biology
  • Oncology
  • Drug Discovery

Background:

  • Accelerated proliferation in solid tumors and hematologic cancers correlates with increased rDNA transcription by RNA polymerase I (Pol I).
  • Upregulation of Pol I, often due to oncogene and tumor suppressor alterations, is crucial for cancer cell survival.
  • Targeting Pol I offers a therapeutic strategy for selective inhibition in cancer treatment.

Purpose of the Study:

  • To identify and characterize a novel inhibitor of RNA Pol I transcription.
  • To evaluate the preclinical efficacy of CX-5461 as a potential anticancer agent.

Main Methods:

  • In vitro and in vivo studies were conducted to assess the inhibitory effects of CX-5461 on Pol I transcription.
  • Pharmacokinetic and pharmacodynamic properties of CX-5461 were evaluated.
  • Tumor growth efficacy models were utilized to determine in vivo activity.

Main Results:

  • CX-5461 (7c) was identified as a potent and selective inhibitor of RNA Pol I transcription.
  • The compound demonstrated oral bioavailability.
  • CX-5461 exhibited in vivo activity in tumor growth efficacy models.

Conclusions:

  • CX-5461 represents a first-in-class, orally bioavailable inhibitor of RNA Pol I transcription.
  • Preclinical data support the development of CX-5461 for the treatment of various cancers.
  • CX-5461 shows potential as a novel anticancer therapeutic targeting Pol I.
Keywords:
CX-5461RNA polymerase Ip53rRNA

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