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Activity of a Py-Im polyamide targeted to the estrogen response element.

Authors
Type
Published Article
Journal
Molecular Cancer Therapeutics
Publisher
American Association for Cancer Research
Publication Date
Feb 26, 2013
Volume
12
Issue
5
Pages
675–684
Identifiers
DOI: 10.1158/1535-7163.MCT-12-1040
PMID: 23443804
PMCID: PMC3651785
Source
UCSC Aging biomedical-ucsc
License
Green

Abstract

Pyrrole-imidazole (Py-Im) polyamides are a class of programmable DNA minor groove binders capable of modulating the activity of DNA-binding proteins and affecting changes in gene expression. Estrogen receptor alpha (ERα) is a ligand-activated hormone receptor that binds as a homodimer to estrogen response elements (ERE) and is a driving oncogene in a majority of breast cancers. We tested a selection of structurally similar Py-Im polyamides with differing DNA sequence specificity for activity against 17β-estadiol (E2)-induced transcription and cytotoxicity in ERα positive, E2-stimulated T47DKBluc cells, which express luciferase under ERα control. The most active polyamide targeted the sequence 5 -WGGWCW-3 (W = A or T), which is the canonical ERE half site. Whole transcriptome analysis using RNA-Seq revealed that treatment of E2-stimulated breast cancer cells with this polyamide reduced the effects of E2 on the majority of those most strongly affected by E2 but had much less effect on the majority of E2-induced transcripts. In vivo, this polyamide circulated at detectable levels following subcutaneous injection and reduced levels of ER-driven luciferase expression in xenografted tumors in mice after subcutaneous compound administration without significant host toxicity.

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