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.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Cell Line, Tumor
-
Drug Screening Assays, Antitumor / methods
-
Feasibility Studies
-
High-Throughput Screening Assays / methods*
-
Humans
-
Male
-
Prostatic Neoplasms / drug therapy*
-
Prostatic Neoplasms / genetics
-
Prostatic Neoplasms / metabolism*
-
Protein Interaction Domains and Motifs / drug effects
-
RNA-Binding Protein EWS / antagonists & inhibitors*
-
RNA-Binding Protein EWS / genetics
-
RNA-Binding Protein EWS / metabolism
-
Recombinant Proteins / drug effects
-
Recombinant Proteins / genetics
-
Recombinant Proteins / metabolism
-
Small Molecule Libraries
-
Transcriptional Regulator ERG / antagonists & inhibitors
-
Transcriptional Regulator ERG / genetics
-
Transcriptional Regulator ERG / metabolism
Substances
-
ERG protein, human
-
EWSR1 protein, human
-
RNA-Binding Protein EWS
-
Recombinant Proteins
-
Small Molecule Libraries
-
Transcriptional Regulator ERG