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

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.