(GGAA)3-Based TF-PROTACs Enable Targeted Degradation of ETV6 to Inhibit Ewing Sarcoma Growth

  • J Am Chem Soc. 2025 Apr 23;147(16):13396-13404. doi: 10.1021/jacs.4c18484.
Zhichuan Zhu  1  2 ,  He Chen  3 ,  Xing Qiu  3 ,  H Umit Kaniskan  3 ,  Ling Xie  1  2 ,  Xian Chen  1  2 ,  Jian Jin  3 ,  Pengda Liu  1  2
Affiliations
  • 1. Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.
  • 2. Department of Biochemistry and Biophysics, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.
  • 3. Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences, Oncological Sciences and Neuroscience, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States.
PMID: 40215343 DOI: 10.1021/jacs.4c18484
Abstract

Ewing sarcoma is a rare pediatric Cancer primarily driven by the EWS::FLI1 oncofusion transcription factor. Despite being an ideal drug target, EWS::FLI1 has proven challenging to inhibit with conventional approaches. Recent studies identified ETV6 as a vulnerability in Ewing sarcoma, where it competes with EWS::FLI1 at short GGAA repeats to restrain EWS::FLI1 function. However, no therapies targeting ETV6 have been developed. In this study, we report the discovery of a unique (GGAA)3 DNA oligonucleotide that specifically binds to ETV6 but not EWS::FLI1. We developed (GGAA)3-based TF-PROTACs, termed d(GGAA)3s, by coupling (GGAA)3 with VHL ligands. d(GGAA)3s effectively degraded endogenous ETV6 but not EWS::FLI1 proteins in Ewing sarcoma cells, thus suppressing Ewing sarcoma growth. Mechanistically, d(GGAA)3s enhanced oncogenic EWS::FLI1 transcriptional activity, inducing cellular stress and cell death. Additionally, d(GGAA)3s sensitized Ewing sarcoma cells to standard chemotherapy, suggesting their potential use in combination therapies. Beyond Ewing sarcoma, d(GGAA)3s also targeted ETV6-fusion proteins found in breast Cancer, broadening their potential clinical applications. In summary, d(GGAA)3s represent a nucleotide-based approach for degrading ETV6, inhibiting Ewing sarcoma growth and targeting ETV6-dependent cancers. This strategy offers a promising therapeutic avenue for Ewing sarcoma and Other malignancies involving ETV6 fusions.

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