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Proc Natl Acad Sci U S A. 2013 Jan 29;110(5):1863-8. doi: 10.1073/pnas.1222035110. Epub 2013 Jan 14.

Antitumor activity of a pyrrole-imidazole polyamide.

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Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125, USA.


Many cancer therapeutics target DNA and exert cytotoxicity through the induction of DNA damage and inhibition of transcription. We report that a DNA minor groove binding hairpin pyrrole-imidazole (Py-Im) polyamide interferes with RNA polymerase II (RNAP2) activity in cell culture. Polyamide treatment activates p53 signaling in LNCaP prostate cancer cells without detectable DNA damage. Genome-wide mapping of RNAP2 binding shows reduction of occupancy, preferentially at transcription start sites, but occupancy at enhancer sites is unchanged. Polyamide treatment results in a time- and dose-dependent depletion of the RNAP2 large subunit RPB1 that is preventable with proteasome inhibition. This polyamide demonstrates antitumor activity in a prostate tumor xenograft model with limited host toxicity.

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