Proximity-Induced Rewiring of Oncogenic Kinase Triggers Apoptosis

The active site’s electric field is integral to
enzymatic
catalysis (e.g., substrate recognition), and nature employs charge-altering
post-translational modifications (e.g., phosphorylation) to perturb
this electric field and regulate enzymes. A chromosomal translocation
converts Abelson kinase (ABL) to BCR-ABL, the hyperactivity of which
drives several cancers. Here, we developed a small molecule, BRD8833,
that induces BCR-ABL phosphorylation, which perturbs its active site’s
electric field with loss of hyperactivity. Unlike “occupancy-driven”
inhibitors that require stoichiometric concentrations, BRD8833 operates
through an event-driven, substoichiometric mechanism by inducing the
proximity between two BCR-ABL molecules to trigger the inhibitory
phosphorylation and selective apoptosis of BCR-ABL-dependent cancer
cells. Furthermore, BRD8833 is effective against other oncogenic ABL
fusions or clinically observed resistance mutations, including those
to occupancy-driven drugs with the same binding site as BRD8833, suggesting
differences in their resistance mechanisms. These studies lay the
foundation for electric-field and “event-driven” modalities
to control hyperactive enzymes with orthogonal resistance mechanisms
to occupancy-driven drugs.