Identification of a non-inhibitory aptameric ligand to CRL2ZYG11B E3 ligase for targeted protein degradation

Zhihao Yang, Miao Chen, Ruixin Ge, Ping Zhou, Wei Pan, Jiayi Song, Shuwen Ma, Song Chen, Chenyu Xu, Mengyu Zhou, Wenyi Mi, Hua Ni, He Chen, Xue Yao, Xifeng Dong, Yan Chen, Jun Zhou, Chenghao Xuan (), Cheng Dong (), Hua Yan () and Songbo Xie ()
Additional contact information
Zhihao Yang: Tianjin Medical University General Hospital
Miao Chen: Shandong University of Technology
Ruixin Ge: Shandong Normal University
Ping Zhou: Shandong Normal University
Wei Pan: Shandong Normal University
Jiayi Song: Tianjin Medical University General Hospital
Shuwen Ma: Tianjin Medical University General Hospital
Song Chen: Tianjin Medical University General Hospital
Chenyu Xu: Nankai University
Mengyu Zhou: Tianjin Medical University
Wenyi Mi: Tianjin Medical University
Hua Ni: Nankai University
He Chen: Tianjin Medical University
Xue Yao: Tianjin Medical University General Hospital
Xifeng Dong: Tianjin Medical University General Hospital
Yan Chen: Shandong Normal University
Jun Zhou: Shandong Normal University
Chenghao Xuan: Tianjin Medical University General Hospital
Cheng Dong: Tianjin Medical University General Hospital
Hua Yan: Tianjin Medical University General Hospital
Songbo Xie: Tianjin Medical University General Hospital

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract As a crucial element of proteolysis targeting chimeras (PROTACs), the choice of E3 ubiquitin ligase significantly influences degradation efficacy and selectivity. However, the available arsenal of E3 ligases for PROTAC development remains underexplored, severely limiting the scope of targeted protein degradation. In this study, we identify a non-inhibitory aptamer targeting ZYG11B, a substrate receptor of the Cullin 2-RING ligase complex, as an E3 warhead for targeted protein degradation. This aptamer-based PROTAC platform, termed ZATAC, is facilely produced through bioorthogonal chemistry or self-assembly and shows promise in eliminating several undruggable target proteins, including nucleolin (NCL), SRY-box transcription factor 2 (SOX2), and mutant p53-R175H, underscoring its universality and versatility. To specifically deliver ZATACs into cancer cells, we further develop DNA three-way junction-based ZATACs (3WJ-ZATACs) by integrating an additional aptamer that selectively recognizes the protein overexpressed on the surface of cancer cells. The 3WJ-ZATACs demonstrate in vivo tumor-specific distribution and achieve dual-target degradation, thereby suppressing tumor growth without causing noticeable toxicity. In summary, ZATACs represent a general, modular, and straightforward platform for targeted protein degradation, offering insights into the potential of other untapped E3 ligases.

Date: 2025
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DOI: 10.1038/s41467-025-57823-5

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