Rewiring the fusion oncoprotein EWS/FLI1 in Ewing sarcoma with bivalent small molecules

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Deregulated transcription, driven by fusion transcription factors, is common in pediatric cancers.
• Targeting transcription factors is difficult due to their lack of druggable pockets.
• Chemically induced proximity offers a new strategy to control gene expression.

Purpose of the Study:

• To develop a novel small molecule, EB-TCIP, for targeting EWS/FLI1 in Ewing sarcoma.
• To demonstrate the potential of chemically induced proximity for rewiring fusion transcription factors.
• To explore new therapeutic avenues for pediatric malignancies driven by aberrant transcription.

Main Methods:

• Development of a bivalent small molecule, EB-TCIP.
• Recruitment of FKBP12-tagged EWS/FLI1 to BCL6-bound DNA sites.
• Assessment of BCL6 target gene expression and ternary complex formation.

Main Results:

• EB-TCIP successfully recruits FKBP-EWS/FLI1 to specific DNA sites.
• Rapid expression of BCL6 target genes was observed.
• The molecule's activity was dependent on ternary complex formation and cell-specific expression of FKBP-EWS/FLI1.

Conclusions:

• EWS/FLI1 can be effectively relocalized on chromatin to induce gene expression.
• This proof-of-concept study validates the use of bivalent molecules for targeting fusion transcription factors.
• Findings provide a foundation for developing novel therapeutics for cancers driven by aberrant transcription.