Rewiring the fusion oncoprotein EWSR1::FLI1 in Ewing sarcoma with bivalent small molecules
Targeting fusion transcription factors, such as EWSR1::FLI1 in Ewing sarcoma, with these bivalent compounds may open new therapeutic avenues.
Dysregulated transcription is a defining hallmark of cancer. In this proof‑of‑concept study, the authors demonstrate that bivalent small molecules (TCIPs) can redirect the DNA‑binding fusion transcription factor EWSR1::FLI1 to BCL6‑bound loci, inducing expression of pro‑apoptotic genes and opening a new therapeutic strategy for Ewing sarcoma.
Ewing sarcoma is driven almost exclusively by the EWSR1::FLI1 fusion, yet small‑molecule inhibitors of this transcription factor have been elusive. Coupling a FKBP12^F36V binder with a BCL6 inhibitor (EB‑TCIP) relocalizes EWSR1::FLI1 to new chromatin sites, activating genes that promote apoptosis. This shows a new drug‑gable paradigm for transcription‑factor‑dependent cancers.
Bizonyítékszint: Klinikai vizsgálat. Formális klinikai vizsgálati eredmény.
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