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Updated: Feb 5, 2026
High-throughput Screening for Chemical Modulators of Post-transcriptionally Regulated Genes
Published on: March 3, 2015
Development of High-Throughput Screening Assays for Inhibitors of ETS Transcription Factors
Simon L Currie1, Steven L Warner2,3, Hariprasad Vankayalapati2,4
11 Department of Oncological Sciences, School of Medicine, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
Abstract:
ETS transcription factors from the ERG and ETV1/4/5 subfamilies are overexpressed in the majority of prostate cancer patients and contribute to disease progression. Here, we have developed two in vitro assays for the interaction of ETS transcription factors with DNA that are amenable to high-throughput screening. Using ETS1 as a model, we applied these assays to screen 110 compounds derived from a high-throughput virtual screen. We found that the use of lower-affinity DNA binding sequences, similar to those that ERG and ETV1 bind to in prostate cells, allowed for higher inhibition from many of these test compounds. Further pilot experiments demonstrated that the in vitro assays are robust for ERG, ETV1, and ETV5, three of the ETS transcription factors that are overexpressed in prostate cancer.
Insights
We developed new high-throughput screening assays to find drugs targeting ETS transcription factors, which drive prostate cancer progression. These assays successfully identified compounds inhibiting key ETS factors like ERG and ETV1, offering new therapeutic avenues.
Area of Science:
- Molecular Biology
- Cancer Research
- Drug Discovery
Background:
- ETS transcription factors, including ERG and ETV1/4/5, are frequently overexpressed in prostate cancer.
- These overexpressed factors play a significant role in the progression of prostate cancer.
- Targeting these ETS factors presents a potential therapeutic strategy.
Purpose of the Study:
- To develop novel in vitro assays for high-throughput screening of ETS transcription factor-DNA interactions.
- To identify compounds that inhibit the activity of ETS transcription factors implicated in prostate cancer.
Main Methods:
- Development of two high-throughput screening assays to measure ETS transcription factor-DNA binding.
- Screening of 110 compounds using ETS1 as a model, with a focus on lower-affinity DNA binding sequences.
- Validation of assay robustness for ERG, ETV1, and ETV5, key ETS factors in prostate cancer.
Main Results:
- The developed in vitro assays are suitable for high-throughput screening.
- Using lower-affinity DNA binding sequences enhanced compound inhibition, mimicking binding sites of ERG and ETV1 in prostate cells.
- The assays demonstrated robustness for multiple ETS transcription factors (ERG, ETV1, ETV5) overexpressed in prostate cancer.
Conclusions:
- Novel high-throughput screening assays for ETS transcription factor-DNA interactions have been successfully developed.
- These assays facilitate the identification of inhibitors targeting ETS factors crucial for prostate cancer progression.
- The findings support the development of targeted therapies for prostate cancer by inhibiting specific ETS transcription factors.
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