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

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.