title: Antitumor activity of a pyrrole-imidazole polyamide.
abstract: 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.
authors: Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
authors: Fei
authors: F
authors: Yang
authors: Nicholas G
authors: NG
authors: Nickols
authors: Benjamin C
authors: BC
authors: Li
authors: Georgi K
authors: GK
authors: Marinov
authors: Jonathan W
authors: JW
authors: Said
authors: Peter B
authors: PB
authors: Dervan
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007093:Imidazoles / Q000737:chemistry; D015151:Immunoblotting; D053631:Interleukin Receptor Common gamma Subunit / Q000172:deficiency / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D009757:Nylons / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D061988:Proteasome Inhibitors / Q000494:pharmacology; D021122:Protein Subunits / Q000037:antagonists & inhibitors / Q000378:metabolism; D011758:Pyrroles / Q000737:chemistry; D012319:RNA Polymerase II / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C507942:Il2rg protein, mouse; D007093:Imidazoles; D053631:Interleukin Receptor Common gamma Subunit; D009757:Nylons; D061988:Proteasome Inhibitors; D021122:Protein Subunits; D011758:Pyrroles; D016159:Tumor Suppressor Protein p53; C029899:imidazole; D012319:RNA Polymerase II