Targeting RNA Polymerase I with an Oral Small Molecule CX-5461 Inhibits Ribosomal RNA Synthesis and Solid Tumor Growth
2010; American Association for Cancer Research; Volume: 71; Issue: 4 Linguagem: Inglês
10.1158/0008-5472.can-10-1728
ISSN1538-7445
AutoresDenis Drygin, Amy Lin, Josh Bliesath, Caroline B. Ho, Sean O’Brien, Chris Proffitt, Mayuko Omori, Mustapha Haddach, Michael K. Schwaebe, Adam Siddiqui-Jain, Nicole Streiner, Jaclyn Quin, Elaine Sanij, Megan J. Bywater, Ross D. Hannan, David M. Ryckman, Kenna Anderes, William G. Rice,
Tópico(s)RNA Interference and Gene Delivery
ResumoAbstract 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. Cancer Res; 71(4); 1418–30. ©2010 AACR.
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