biostudies-literatureBond MJNIH Office of the DirectorNational Cancer InstituteNCI NIH HHSNIH HHSNIGMS NIH HHS44739-44758https://www.ebi.ac.uk/biostudies/studies/S-EPMC12851799biostudies-literatureUnknown147(49)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, <b>EB-TCIP</b>, that recruits FKBP12^F36V-tagged EWSR1::FLI1 to DNA sites bound by the transcriptional regulator BCL6, leading to rapid chromatin remodeling and expression Journal of the American Chemical SocietyRewiring the Fusion Oncoprotein EWSR1::FLI1 in Ewing Sarcoma with Bivalent Small Molecules.PMC12851799F32 CA2847501S10OD036228R01 CA283395S10 OD028697R35 CA283977T32 GM136631U54 CA231637S10 OD036228Howard BGourisankar SStegmaier KDwyer BGKarim BAAlexe GDiGiovanni GSarott RCJones HMGolden RPGray NSRoss KBond MJfalseRewiring the Fusion Oncoprotein EWSR1::FLI1 in Ewing Sarcoma with Bivalent Small Molecules.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, <b>EB-TCIP</b>, that recruits FKBP12^F36V-tagged EWSR1::FLI1 to DNA sites bound by the transcriptional regulator BCL6, leading to rapid chromatin remodeling and expression 2025-01-01T00:00:00Z2025 Dec2026-07-15T13:48:00.652Z2026-07-05T03:08:40.569ZS-EPMC128517994130721010.1021/jacs.5c05634