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Updated: Dec 9, 2025
Mapping the Structure-Function Relationships of Disordered Oncogenic Transcription Factors Using Transcriptomic Analysis
Published on: June 27, 2020
--A high-throughput screen identifies inhibitors of the interaction between the oncogenic transcription factor ERG
Taylor R Nicholas1, Jingwei Meng2, Benjamin M Greulich3
1Department of Biology, Indiana University, Bloomington, Indiana, United States of America.
Abstract:
Aberrant expression of the transcription factor ERG is a key driving event in approximately one-half of all of prostate cancers. Lacking an enzymatic pocket and mainly disordered, the structure of ERG is difficult to exploit for therapeutic design. We recently identified EWS as a specific interacting partner of ERG that is required for oncogenic function. In this study, we aimed to target this specific protein-protein interaction with small molecules. A high-throughput screening (HTS) strategy was implemented to identify potential protein-protein interaction inhibitors. Secondary assays verified the function of several hit compounds, and one lead compound inhibited ERG-mediated phenotypes in prostate cells. This is the first study aimed at targeting the ERG-EWS protein-protein interaction for the development of a small molecule-based prostate cancer therapy.
Insights
Researchers targeted the ERG-EWS protein interaction, crucial for prostate cancer growth, using small molecules. A lead compound successfully inhibited ERG-driven cancer cell activity, offering a new therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Aberrant expression of the ERG (E-twenty-six related gene) transcription factor drives approximately 50% of prostate cancers.
- The disordered structure of ERG presents challenges for traditional drug design targeting its enzymatic pocket.
- The EWS (Ewing sarcoma breakpoint region 1) protein has been identified as essential for ERG's oncogenic function.
Purpose of the Study:
- To develop novel small molecule inhibitors targeting the protein-protein interaction between ERG and EWS.
- To identify compounds that disrupt the oncogenic signaling mediated by the ERG-EWS complex in prostate cancer.
Main Methods:
- A high-throughput screening (HTS) approach was employed to identify inhibitors of the ERG-EWS interaction.
- Secondary assays were utilized to validate the functional activity of identified hit compounds.
- Prostate cancer cell models were used to assess the efficacy of lead compounds in inhibiting ERG-mediated phenotypes.
Main Results:
- Several compounds were identified as potential inhibitors of the ERG-EWS protein-protein interaction.
- One lead compound demonstrated significant inhibition of ERG-mediated phenotypes in prostate cancer cells.
- This study represents the first effort to therapeutically target the ERG-EWS interaction.
Conclusions:
- Targeting the ERG-EWS protein-protein interaction is a viable strategy for prostate cancer therapy.
- The identified lead compound shows promise for further development into a small molecule-based treatment.
- This research opens a new avenue for developing therapies against ERG-driven prostate cancers.
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