Rewiring the Fusion Oncoprotein EWSR1::FLI1 in Ewing Sarcoma with Bivalent Small Molecules.

ABSTRACT: Dysregulated transcription is a defining hallmark of cancer. Recently, novel chemically induced proximity approaches have enabled the rewiring of transcriptional machinery to drive expression of pro-apoptotic genes using bivalent small molecules. In this work, we demonstrate that this strategy is amenable to relocalizing DNA bound transcriptional machinery, such as fusion transcription factors that commonly drive pediatric malignancies. Targeting fusion transcription factors, such as EWSR1::FLI1 in Ewing sarcoma, with these bivalent compounds may open new therapeutic avenues. Here, we develop a small molecule, EB-TCIP, that recruits FKBP12^F36V-tagged EWSR1::FLI1 to DNA sites bound by the transcriptional regulator BCL6, leading to rapid chromatin remodeling and expression

SUBMITTER: Bond MJ 

PROVIDER: S-EPMC12851799 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature