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Anticancer activity of CX-3543: a direct inhibitor of rRNA biogenesis.
Cancer Res. 2009 Oct 01; 69(19):7653-61.CR

Abstract

Hallmark deregulated signaling in cancer cells drives excessive ribosome biogenesis within the nucleolus, which elicits unbridled cell growth and proliferation. The rate-limiting step of ribosome biogenesis is synthesis of rRNA (building blocks of ribosomes) by RNA Polymerase I (Pol I). Numerous kinase pathways and products of proto-oncogenes can up-regulate Pol I, whereas tumor suppressor proteins can inhibit rRNA synthesis. In tumorigenesis, activating mutations in certain cancer-associated kinases and loss-of-function mutations in tumor suppressors lead to deregulated signaling that stimulates Pol I transcription with resultant increases in ribosome biogenesis, protein synthesis, cell growth, and proliferation. Certain anticancer therapeutics, such as cisplatin and 5-fluorouracil, reportedly exert, at least partially, their activity through disruption of ribosome biogenesis, yet many prime targets for anticancer drugs within the ribosome synthetic machinery of the nucleolus remain largely unexploited. Herein, we describe CX-3543, a small molecule nucleolus-targeting agent that selectively disrupts nucleolin/rDNA G-quadruplex complexes in the nucleolus, thereby inhibiting Pol I transcription and inducing apoptosis in cancer cells. CX-3543 is the first G-quadruplex interactive agent to enter human clinical trials, and it is currently under evaluation against carcinoid/neuroendocrine tumors in a phase II clinical trial.

Authors+Show Affiliations

Cylene Pharmaceuticals, Inc., San Diego, CA 92121, 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 available

Pub Type(s)

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

Language

eng

PubMed ID

19738048

Citation

Drygin, Denis, et al. "Anticancer Activity of CX-3543: a Direct Inhibitor of rRNA Biogenesis." Cancer Research, vol. 69, no. 19, 2009, pp. 7653-61.
Drygin D, Siddiqui-Jain A, O'Brien S, et al. Anticancer activity of CX-3543: a direct inhibitor of rRNA biogenesis. Cancer Res. 2009;69(19):7653-61.
Drygin, D., Siddiqui-Jain, A., O'Brien, S., Schwaebe, M., Lin, A., Bliesath, J., Ho, C. B., Proffitt, C., Trent, K., Whitten, J. P., Lim, J. K., Von Hoff, D., Anderes, K., & Rice, W. G. (2009). Anticancer activity of CX-3543: a direct inhibitor of rRNA biogenesis. Cancer Research, 69(19), 7653-61. https://doi.org/10.1158/0008-5472.CAN-09-1304
Drygin D, et al. Anticancer Activity of CX-3543: a Direct Inhibitor of rRNA Biogenesis. Cancer Res. 2009 Oct 1;69(19):7653-61. PubMed PMID: 19738048.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Anticancer activity of CX-3543: a direct inhibitor of rRNA biogenesis. AU - Drygin,Denis, AU - Siddiqui-Jain,Adam, AU - O'Brien,Sean, AU - Schwaebe,Michael, AU - Lin,Amy, AU - Bliesath,Josh, AU - Ho,Caroline B, AU - Proffitt,Chris, AU - Trent,Katy, AU - Whitten,Jeffrey P, AU - Lim,John K C, AU - Von Hoff,Daniel, AU - Anderes,Kenna, AU - Rice,William G, Y1 - 2009/09/08/ PY - 2009/9/10/entrez PY - 2009/9/10/pubmed PY - 2009/12/16/medline SP - 7653 EP - 61 JF - Cancer research JO - Cancer Res. VL - 69 IS - 19 N2 - Hallmark deregulated signaling in cancer cells drives excessive ribosome biogenesis within the nucleolus, which elicits unbridled cell growth and proliferation. The rate-limiting step of ribosome biogenesis is synthesis of rRNA (building blocks of ribosomes) by RNA Polymerase I (Pol I). Numerous kinase pathways and products of proto-oncogenes can up-regulate Pol I, whereas tumor suppressor proteins can inhibit rRNA synthesis. In tumorigenesis, activating mutations in certain cancer-associated kinases and loss-of-function mutations in tumor suppressors lead to deregulated signaling that stimulates Pol I transcription with resultant increases in ribosome biogenesis, protein synthesis, cell growth, and proliferation. Certain anticancer therapeutics, such as cisplatin and 5-fluorouracil, reportedly exert, at least partially, their activity through disruption of ribosome biogenesis, yet many prime targets for anticancer drugs within the ribosome synthetic machinery of the nucleolus remain largely unexploited. Herein, we describe CX-3543, a small molecule nucleolus-targeting agent that selectively disrupts nucleolin/rDNA G-quadruplex complexes in the nucleolus, thereby inhibiting Pol I transcription and inducing apoptosis in cancer cells. CX-3543 is the first G-quadruplex interactive agent to enter human clinical trials, and it is currently under evaluation against carcinoid/neuroendocrine tumors in a phase II clinical trial. SN - 1538-7445 UR - https://www.unboundmedicine.com/medline/citation/19738048/Anticancer_activity_of_CX_3543:_a_direct_inhibitor_of_rRNA_biogenesis_ L2 - http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=19738048 DB - PRIME DP - Unbound Medicine ER -