Global PROTAC Toolbox for Degrading BCR–ABL Overcomes Drug-Resistant Mutants and Adverse Effects

TLDR

BCR–ABL fusion drives Ph+ leukemias, yet ABL inhibitors are hampered by resistance and adverse effects, and existing PROTACs have limited activity, especially against the T315I mutant. The study systematically designed a set of unique PROTACs that target all three BCR–ABL binding sites to address drug resistance. The authors engineered dasatinib-, ponatinib-, and asciminib‑based PROTACs, including additional dasatinib variants capable of degrading the T315I mutant. These PROTACs effectively degraded both wild‑type and T315I‑mutated BCR–ABL, showing superior selectivity and fewer adverse effects than inhibitors, highlighting their potential to overcome resistance and safety issues.

Abstract

The BCR–ABL fusion oncoprotein causes chronic myeloid leukemia or acute lymphoblastic leukemia in Ph+ patients because the ABL kinase is constitutively activated. However, current clinical treatment with ABL inhibitors is seriously limited by drug resistance and adverse effects. Although the emerging proteolysis-targeting chimeras (PROTACs) have been introduced to degrade BCR–ABL, most of them showed limited activity and could not overcome the common drug-resistant mutants, especially for T315I mutant. Herein, we systematically designed a set of unique PROTACs by globally targeting all the three binding sites of BCR–ABL, including dasatinib-, ponatinib-, and asciminib-based PROTACs. Our ponatinib-based PROTACs showed practical activity as dasatinib-based PROTACs, while no reported ponatinib-based PROTACs could degrade BCR–ABL before. As a proof of concept, some additional dasatinib-based PROTACs were then designed to degrade T315I mutant too. We provided a global PROTAC toolbox for degrading both wild-type and T315I-mutated BCR–ABL from each binding site. More importantly, these PROTACs showed better selectivity and less adverse effects than the inhibitors, indicating that PROTACs had great potential for overcoming clinical drug resistance and safety issues.