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Cancer Cell Article Demonstrates First Definitive Evidence for Targeting of Pol I as New Approach to Cancer Therapy
Date:7/10/2012

ac later this year."

The Cancer Cell publication highlighted a number of potential competitive advantages of CX-5461.  An unanticipated finding was that malignant cells are considerably more dependent upon maintenance of high levels of Pol I activity than previously believed, and even modest inhibition of Pol I triggers cancer cell death. These results suggest that selective activation of a surveillance pathway to activate p53, using Pol I inhibitors such as CX-5641, is likely to be therapeutically useful in the treatment of a wide range of tumors. In addition, as a cancer-specific inducer of p53, CX-5461 was shown to be 300 times more potent than currently studied non-genotoxic p53 activators with alternate mechanisms.

About Pol I and CX-5461 CX-5461 is a first-in-class, selective small molecule inhibitor of RNA polymerase I (Pol I) that triggers a stress surveillance pathway to activate p53 in cancer cells. The tumor suppressor protein p53, known as "the guardian of the genome," orchestrates cellular responses to diverse stress factors. Activation of this protein can lead to cell cycle arrest or cell death and it is pivotal in determining whether cancer cells proliferate or die. CX-5461 inhibits upregulated Pol I transcription in cancer cells, causing the release of ribosomal proteins (RP) from the nucleolus. These RP then bind to Mdm2, liberating p53 from the Mdm2-p53 complex to induce apoptosis in cancer cells. Non-genotoxic activation of p53 has long been an attractive approach to treating cancers, but it has not yet been successfully exploited in the clinic. CX-5461 has therapeutic potential in both solid tumor and hematological malignancies, yet hematologic cancers, the vast majority of which have wild-type p53 status, are exquisitely sensitive to CX-5461 and represent the clearest path to clinical proof of concept.

About Cylene Pharmaceuticals Cylene Pharmaceuticals is a clinical stage private company developing small molecu
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SOURCE Cylene Pharmaceuticals, Inc.
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