Developing Novel Anticancer DNA-Binding Drugs to Disrupt ETS-Mediated Transcription Associated with Breast Cancer: Use of the C-Fos Serum Response Element as a Model System
Abstract
Disregulated transcription factor (TF) -mediated activation of gene expression can play a key role in oncogenesis, especially in breast cancer. Preventing TF/DNA interactions using small molecule DNA-reactive agents may decrease oncogenic gene expression and potentially halt cancer development. Our goal is to improve DNA-binding drugs' abilities to inhibit specific TF/DNA interactions using the human c-fos promoter's serum response element (SEE) as a target. In an effort to improve drug effectiveness, the novel minor groove-binding fluorescent microgonotropens (FMGTs) were developed. These A/T selective bisbenzimidazole-based agents have polyamine tails that extend to contact DNA's phosphodiester backbone, allowing them to bind with very high affinity. Here, we explore the potential of these agents to inhibit TF/DNA complex formation in a series of increasingly complex assays in the c-fos model and assess whether their ability to contact both groove makes them more effective than classical minor groove-binding drugs. Analyzing these agents using a well-defined gene regulatory element and TFs have provided insight into the relationship between their chemical structure and biological activities and form the basis for further drug development.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jun 01, 2001
- Accession Number
- ADA392049
Entities
People
- Christine M. White
Organizations
- Health Research, Incorporated