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Antitumor activity of a pyrrole-imidazole polyamide

机译:吡咯-咪唑聚酰胺的抗肿瘤活性

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摘要

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. PolyanTide 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.
机译:许多癌症治疗剂靶向DNA并通过诱导DNA损伤和抑制转录发挥细胞毒性作用。我们报告说,DNA小沟结合发夹吡咯-咪唑(Py-Im)聚酰胺干扰细胞培养中的RNA聚合酶II(RNAP2)的活性。 PolyanTide处理可激活LNCaP前列腺癌细胞中的p53信号传导,而不会检测到DNA损伤。 RNAP2结合的全基因组图谱显示减少了占用,优先在转录起始位点,但增强子位点的占用没有变化。聚酰胺处理导致RNAP2大亚基RPB1的时间和剂量依赖性消耗,这可以通过蛋白酶体抑制来预防。该聚酰胺在具有有限宿主毒性的前列腺肿瘤异种移植模型中显示出抗肿瘤活性。

著录项

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  • 作者单位

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

    Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125,Department of Radiation Oncology, David Geffen School of Medicine of the University of California, Los Angeles, CA 90095;

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

    Division of Biology, California Institute of Technology, Pasadena, CA 91125;

    Department of Pathology and Laboratory Medicine, David Geffen School of Medicine of the University of California, Los Angeles, CA 90095;

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

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    minor groove binder; small molecule transcription inhibitor; ChlP-Seq;

    机译:小槽活页夹;小分子转录抑制剂ChlP序列;

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