2. Academic Validation
  3. Identification of a non-inhibitory aptameric ligand to CRL2ZYG11B E3 ligase for targeted protein degradation

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

  • Nat Commun. 2025 Mar 13;16(1):2494. doi: 10.1038/s41467-025-57823-5.
Zhihao Yang # 1,  Miao Chen # 2,  Ruixin Ge 3,  Ping Zhou 3,  Wei Pan 3,  Jiayi Song 4,  Shuwen Ma 4,  Song Chen 4,  Chenyu Xu 5,  Mengyu Zhou 6,  Wenyi Mi 6,  Hua Ni 7,  He Chen 8,  Xue Yao 9,  Xifeng Dong 10,  Yan Chen 3,  Jun Zhou 3 7,  Chenghao Xuan 11 12,  Cheng Dong 13 14,  Hua Yan 15,  Songbo Xie 16 17 18
Affiliations

Affiliations

  • 1 Key Laboratory of Breast Cancer Prevention and Therapy (Ministry of Education); Key Laboratory of Immune Microenvironment and Disease (Ministry of Education); The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Department of Biochemistry and Molecular Biology, Tianjin Medical University; Department of Ophthalmology, Tianjin Medical University General Hospital, Tianjin, China.
  • 2 School of Life Sciences and Medicine, Shandong University of Technology, Zibo, China.
  • 3 Center for Cell Structure and Function, Collaborative Innovation Center of Cell Biology in Universities of Shandong, College of Life Sciences, Shandong Normal University, Jinan, China.
  • 4 Department of Ophthalmology, Ministry of Education International Joint Laboratory of Ocular Diseases, Tianjin Key Laboratory of Ocular Trauma, Tianjin Institute of Eye Health and Eye Diseases, China-UK "Belt and Road" Ophthalmology Joint Laboratory, Tianjin Medical University General Hospital, Tianjin, China.
  • 5 School of Medicine, Nankai University, Tianjin, China.
  • 6 School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.
  • 7 State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Protein Science, Haihe Laboratory of Cell Ecosystem, College of Life Sciences, Nankai University, Tianjin, China.
  • 8 Department of Medicinal Chemistry, Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin, China.
  • 9 Tianjin Key Laboratory of Spine and Spinal Cord, Department of Orthopaedics, Tianjin Medical University General Hospital, Tianjin, China.
  • 10 Department of Hematology, Tianjin Key Laboratory of Bone Marrow Failure and Malignant Hemopoietic Clone Control, Tianjin Institute of Hematology, Tianjin Medical University General Hospital, Tianjin, China.
  • 11 Key Laboratory of Breast Cancer Prevention and Therapy (Ministry of Education); Key Laboratory of Immune Microenvironment and Disease (Ministry of Education); The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Department of Biochemistry and Molecular Biology, Tianjin Medical University; Department of Ophthalmology, Tianjin Medical University General Hospital, Tianjin, China. chenghaoxuan@tmu.edu.cn.
  • 12 School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China. chenghaoxuan@tmu.edu.cn.
  • 13 Key Laboratory of Breast Cancer Prevention and Therapy (Ministry of Education); Key Laboratory of Immune Microenvironment and Disease (Ministry of Education); The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Department of Biochemistry and Molecular Biology, Tianjin Medical University; Department of Ophthalmology, Tianjin Medical University General Hospital, Tianjin, China. dongcheng@tmu.edu.cn.
  • 14 School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China. dongcheng@tmu.edu.cn.
  • 15 Department of Ophthalmology, Ministry of Education International Joint Laboratory of Ocular Diseases, Tianjin Key Laboratory of Ocular Trauma, Tianjin Institute of Eye Health and Eye Diseases, China-UK "Belt and Road" Ophthalmology Joint Laboratory, Tianjin Medical University General Hospital, Tianjin, China. zyyyanhua@tmu.edu.cn.
  • 16 Key Laboratory of Breast Cancer Prevention and Therapy (Ministry of Education); Key Laboratory of Immune Microenvironment and Disease (Ministry of Education); The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Department of Biochemistry and Molecular Biology, Tianjin Medical University; Department of Ophthalmology, Tianjin Medical University General Hospital, Tianjin, China. songboxie@tmu.edu.cn.
  • 17 Center for Cell Structure and Function, Collaborative Innovation Center of Cell Biology in Universities of Shandong, College of Life Sciences, Shandong Normal University, Jinan, China. songboxie@tmu.edu.cn.
  • 18 Department of Ophthalmology, Ministry of Education International Joint Laboratory of Ocular Diseases, Tianjin Key Laboratory of Ocular Trauma, Tianjin Institute of Eye Health and Eye Diseases, China-UK "Belt and Road" Ophthalmology Joint Laboratory, Tianjin Medical University General Hospital, Tianjin, China. songboxie@tmu.edu.cn.
  • # Contributed equally.
PMID: 40082426 DOI: 10.1038/s41467-025-57823-5
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.

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