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  3. ATTEC-mediated degradation of BCR-ABL in chronic myeloid leukemia cells

ATTEC-mediated degradation of BCR-ABL in chronic myeloid leukemia cells

  • Eur J Med Chem. 2026 Feb 5:303:118430. doi: 10.1016/j.ejmech.2025.118430.
Zhiyan Wang 1,  Tingting Xu 2,  Yiying Che 2,  Jun-An Ma 3,  Runqi Jin 2,  Boao Mao 2,  Xinru Lai 2,  Kunrong Mei 4,  Hongxia Zhao 5,  Zhiguang Yuchi 6
Affiliations

Affiliations

  • 1 Department of Molecular Pharmacology, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute & Hospital, Tianjin, 300060, China; State Key Laboratory of Synthetic Biology and Frontiers Science Center for Synthetic Biology, Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, School of Pharmaceutical Science and Technology, Faculty of Medicine, Tianjin University, Tianjin, China.
  • 2 State Key Laboratory of Synthetic Biology and Frontiers Science Center for Synthetic Biology, Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, School of Pharmaceutical Science and Technology, Faculty of Medicine, Tianjin University, Tianjin, China.
  • 3 Department of Chemistry, State Key Laboratory Synthetic Biology, Tianjin University, Tianjin, 300072, China.
  • 4 State Key Laboratory of Synthetic Biology and Frontiers Science Center for Synthetic Biology, Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, School of Pharmaceutical Science and Technology, Faculty of Medicine, Tianjin University, Tianjin, China. Electronic address: kmei@tju.edu.cn.
  • 5 State Key Laboratory of Synthetic Biology and Frontiers Science Center for Synthetic Biology, Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, School of Pharmaceutical Science and Technology, Faculty of Medicine, Tianjin University, Tianjin, China. Electronic address: zhaohongxia@tju.edu.cn.
  • 6 Department of Molecular Pharmacology, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute & Hospital, Tianjin, 300060, China; State Key Laboratory of Synthetic Biology and Frontiers Science Center for Synthetic Biology, Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, School of Pharmaceutical Science and Technology, Faculty of Medicine, Tianjin University, Tianjin, China; Haihe Laboratory of Sustainable Chemical Transformations, Tianjin, China. Electronic address: yuchi@tju.edu.cn.
PMID: 41344112 DOI: 10.1016/j.ejmech.2025.118430
Abstract

Chronic myeloid leukemia (CML) is driven by the Bcr-Abl oncoprotein, which exerts both kinase-dependent and kinase-independent oncogenic functions. However, current tyrosine kinase inhibitors (TKIs) fail to eliminate its non-catalytic activities. Here, we report the rational design and synthesis of autophagosome-tethering chimeras (ATTECs) that selectively degrade Bcr-Abl via the autophagy-lysosome pathway. By conjugating the Bcr-Abl Inhibitor dasatinib with the LC3B-binding ligand GW5074, we engineered eight distinct ATTEC variants with diverse linkers. Among them, DS-PPE-GW, featuring a piperidine-based linker, exhibited the most potent antiproliferation activity in K562 CML cells, with an IC50 of 9.62 nM and a DC50 of 11.6 nM, achieving over 90 % Bcr-Abl degradation. This degradation suppressed phosphorylation of STAT5, a downstream substrate of Bcr-Abl, and significantly inhibited cell proliferation. The activity of DS-PPE-GW was further enhanced by the Autophagy activator rapamycin, confirming its Autophagy dependence. Notably, DS-PPE-GW did not increase global autophagic flux, suggesting selective engagement of pre-existing autophagosomes. These findings demonstrate that strategically designed ATTECs can efficiently degrade Bcr-Abl, targeting both its catalytic and non-catalytic functions, and provide a promising strategy for next-generation CML therapy.

Keywords

Autophagosome-tethering chimeras (ATTECs); BCR-ABL oncoprotein; Chronic myeloid leukemia (CML); Dasatinib; GW5074.

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