DNA Binding Drugs Targeting the Regulatory DNA Binding Site of the ETS Domain Family Transcription Factor.
Abstract
Abnormally expressed ESX and AP-2 have been found in certain breast cancer cell lines that are associated with the overexpression of HER2/neu gene. Amplification and overexpression of HER2/neu is found in 20-30% of primary breast cancers and is correlated with a poor prognosis. In this study, polyamides, minor groove binding compounds, were designed to target the ESX binding site on the HER2/neu promoter to interfere with the gene expression. The effects of polyamides to inhibit the binding of ESX and DNA and associated gene expression were compared with that of distamycin. The results revealed that polyamides were more effective than distamycin to inhibit the ESX-DNA complex formation (25-200 fold). Similarly, in a cell free transcription, polyamides inhibited gene expression from the HER2/neu promoter more strongly than distatnycin. In addition, in vitro transcription time course assay indicated that polyamides constantly associated with DNA to inhibit transcription. In contrast, inhibition of transcription by distamycin was increased relative to the time of incubation. In a conclusion, sequence specific designed polyamides for selected transcription factors are potent inhibitors of transcription factor-DNA complex and transcription. This information can be utilized to futture improve drug specificity and effectiveness as abnormal transcription inhibitors.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 1998
- Accession Number
- ADA352305
Entities
People
- Shu-yuan Chiang
Organizations
- Health Research, Incorporated