Strategic Design of Catalytic Lysine-Targeting Reversible Covalent BCR-ABL Inhibitors

Targeted covalent inhibitors have re-emerged as validated drugs to overcome acquired resistance in cancer treatment. Herein, by using a carbonyl boronic acid (CBA) warhead, we report the structure-based design of BCR-ABL inhibitors via reversible covalent targeting of the catalytic lysine with improved potency against both wild-type and mutant ABL kinases, especially ABLT315I bearing the gatekeeper residue mutation. We show the evolutionarily conserved lysine can be targeted selectively, and the selectivity depends largely on molecular recognition of the non-covalent pharmacophore in this class of inhibitors, probably due to the moderate reactivity of the warhead. We report the first cocrystal structures of covalent inhibitor-ABL kinase domain complexes, providing insights into the interaction of this warhead with the catalytic lysine. We also employed label-free mass spectrometry to evaluate off-targets of our compounds at proteome-wide level in different mammalian cells.

Automated summary

In this study, a carbonyl boronic acid warhead was utilized to design BCR-ABL inhibitors, targeting the catalytic lysine with improved potency against ABL kinases. Selectivity of these inhibitors largely depends on molecular recognition of the non-covalent pharmacophore, and insights into the interaction of the warhead with the catalytic lysine were provided through cocrystal structures. The off-target evaluation of compounds was performed using label-free mass spectrometry in different mammalian cells.