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

Area of Science:

• Medicinal Chemistry
• Molecular Biology
• Biochemistry

Background:

• Targeted covalent inhibitors are crucial for overcoming acquired resistance in cancer therapy.
• The ABL kinase, particularly the T315I mutant, is a key target in chronic myeloid leukemia treatment.

Purpose of the Study:

• To design novel BCR-ABL inhibitors using a carbonyl boronic acid (CBA) warhead for reversible covalent targeting.
• To achieve improved potency against wild-type and mutant ABL kinases, especially the gatekeeper T315I mutation.

Main Methods:

• Structure-based drug design utilizing a CBA warhead.
• Co-crystallization of inhibitor-ABL kinase domain complexes.
• Label-free mass spectrometry for proteome-wide off-target evaluation.

Main Results:

• Demonstrated improved potency of CBA-based inhibitors against wild-type and mutant ABL kinases, including ABL^T315I.
• Revealed selective targeting of the evolutionarily conserved lysine residue, dependent on non-covalent pharmacophore interactions.
• Provided the first co-crystal structures of covalent inhibitor-ABL kinase domain complexes, elucidating warhead-lysine interactions.

Conclusions:

• The CBA warhead enables effective reversible covalent inhibition of ABL kinases, including resistant mutants.
• Structure-based design and pharmacophore recognition are key for achieving selectivity and potency.
• These findings offer a promising avenue for developing next-generation cancer therapeutics against resistant kinases.