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Targeting RNA polymerase I with an oral small molecule CX-5461 inhibits ribosomal RNA synthesis and solid tumor growth.
Cancer Res 2011; 71(4):1418-30CR

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.

Authors+Show Affiliations

Cylene Pharmaceuticals, Inc., San Diego, California, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21159662

Citation

Drygin, Denis, et al. "Targeting RNA Polymerase I With an Oral Small Molecule CX-5461 Inhibits Ribosomal RNA Synthesis and Solid Tumor Growth." Cancer Research, vol. 71, no. 4, 2011, pp. 1418-30.
Drygin D, Lin A, Bliesath J, et al. Targeting RNA polymerase I with an oral small molecule CX-5461 inhibits ribosomal RNA synthesis and solid tumor growth. Cancer Res. 2011;71(4):1418-30.
Drygin, D., Lin, A., Bliesath, J., Ho, C. B., O'Brien, S. E., Proffitt, C., ... Rice, W. G. (2011). Targeting RNA polymerase I with an oral small molecule CX-5461 inhibits ribosomal RNA synthesis and solid tumor growth. Cancer Research, 71(4), pp. 1418-30. doi:10.1158/0008-5472.CAN-10-1728.
Drygin D, et al. 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. PubMed PMID: 21159662.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Targeting RNA polymerase I with an oral small molecule CX-5461 inhibits ribosomal RNA synthesis and solid tumor growth. AU - Drygin,Denis, AU - Lin,Amy, AU - Bliesath,Josh, AU - Ho,Caroline B, AU - O'Brien,Sean E, AU - Proffitt,Chris, AU - Omori,Mayuko, AU - Haddach,Mustapha, AU - Schwaebe,Michael K, AU - Siddiqui-Jain,Adam, AU - Streiner,Nicole, AU - Quin,Jaclyn E, AU - Sanij,Elaine, AU - Bywater,Megan J, AU - Hannan,Ross D, AU - Ryckman,David, AU - Anderes,Kenna, AU - Rice,William G, Y1 - 2010/12/15/ PY - 2010/12/17/entrez PY - 2010/12/17/pubmed PY - 2011/4/28/medline SP - 1418 EP - 30 JF - Cancer research JO - Cancer Res. VL - 71 IS - 4 N2 - 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. SN - 1538-7445 UR - https://www.unboundmedicine.com/medline/citation/21159662/Targeting_RNA_polymerase_I_with_an_oral_small_molecule_CX_5461_inhibits_ribosomal_RNA_synthesis_and_solid_tumor_growth_ L2 - http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=21159662 DB - PRIME DP - Unbound Medicine ER -