Phosphorylation-inducing chimera rewires oncogenic kinase to trigger apoptosis.

ABSTRACT: Hyperactive enzymes drive the pathology of several diseases, and classically, "occupancy-driven" drugs (e.g., active site or allosteric inhibitors) are used to target these enzymes. However, the stoichiometric nature of such inhibitors and the emergence of resistance highlight the need for new modalities. Here, we report a Phosphorylation-Inducing Chimeric Small molecule (PHICS) that rewires the hyperactivity of an oncogenic kinase, BCR-ABL, to phosphorylate its active site residue. Molecular dynamics simulations suggest this phosphorylation inhibits BCR-ABL by inducing electrostatic rearrangements of its active site. This "event-driven" mechanism selectively induces apoptosis of BCR-ABL-dependent cancer cells at substoichiometric concentrations (vs. stoichiometric concentrations of occupa

SUBMITTER: Merz ML 

PROVIDER: S-EPMC12259158 | biostudies-literature | 2025 Jun

REPOSITORIES: biostudies-literature