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

The BCR-ABL fusion oncoprotein causes CML or some ALL in Ph+ patients because the ABL kinase is constitutively activated. However, current clinical treatment with ABL inhibitors is seriously limited by the drug resistance and adverse effects. Although the emerging PROTACs has been introduced to degrade BCR-ABL, most of them showed limited activity and couldn't overcome the common drug-resistant mutants, especially for the T315I mutant. Herein, we systematically designed a set of unique PROTACs by globally targeting all the 3 binding sites of BCR-ABL including dasatinib-, ponatinib- and asciminb-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 inhibitors, indicating that PROTACs had a great potential for overcoming clinical drug resistance and safety issues.

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S1490 Ponatinib (AP24534) Ponatinib (AP24534) is a novel, potent multi-target inhibitor of Abl, PDGFRα, VEGFR2, FGFR1 and Src with IC50 of 0.37 nM, 1.1 nM, 1.5 nM, 2.2 nM and 5.4 nM in cell-free assays, respectively. Ponatinib (AP24534) inhibits autophagy.

Related Targets

FGFR Src VEGFR Bcr-Abl PDGFR Autophagy