--A high-throughput screen identifies inhibitors of the interaction between the oncogenic transcription factor ERG and the cofactor EWS.

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.

• Authors: Taylor R Nicholas, Jingwei Meng, Benjamin M Greulich, Teresa Stevie Morris, Peter C Hollenhorst
• Journal: PloS one (PLoS One) Vol. 15 Issue 9 Pg. e0238999 ( 2020) ISSN: 1932-6203 [Electronic] United States
• PMID: 32915889 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• ERG protein, human
• EWSR1 protein, human
• RNA-Binding Protein EWS
• Recombinant Proteins
• Small Molecule Libraries
• Transcriptional Regulator ERG

Topics

• Cell Line, Tumor
• Drug Screening Assays, Antitumor (methods)
• Feasibility Studies
• High-Throughput Screening Assays (methods)
• Humans
• Male
• Prostatic Neoplasms (drug therapy, genetics, metabolism)
• Protein Interaction Domains and Motifs (drug effects)
• RNA-Binding Protein EWS (antagonists & inhibitors, genetics, metabolism)
• Recombinant Proteins (drug effects, genetics, metabolism)
• Small Molecule Libraries
• Transcriptional Regulator ERG (antagonists & inhibitors, genetics, metabolism)