Phosphorylation-inducing chimera rewires oncogenic kinase to trigger apoptosis

Area of Science:

• Biochemistry
• Molecular Biology
• Drug Discovery

Background:

• Hyperactive enzymes are implicated in numerous diseases.
• Current drugs (occupancy-driven inhibitors) face challenges like stoichiometric requirements and resistance.
• Novel therapeutic modalities are needed to target enzyme hyperactivity.

Purpose of the Study:

• To introduce a new class of drugs called Phosphorylation-Inducing Chimeric Small molecules (PHICS).
• To investigate the mechanism of PHICS in inhibiting the oncogenic kinase BCR-ABL.
• To evaluate the efficacy of PHICS against drug-resistant mutations and other oncogenic fusions.

Main Methods:

• Design and synthesis of Phosphorylation-Inducing Chimeric Small molecule (PHICS).
• Utilizing molecular dynamics simulations to elucidate the inhibition mechanism.
• In vitro testing of PHICS against BCR-ABL-dependent cancer cells and resistance mutations.

Main Results:

• PHICS effectively inhibits BCR-ABL by inducing phosphorylation of its active site residue.
• This phosphorylation event triggers electrostatic rearrangements, leading to enzyme inhibition.
• PHICS demonstrates efficacy against various BCR-ABL fusions and resistance mutations, with orthogonal resistance mechanisms.
• The event-driven approach shows selective apoptosis induction in cancer cells at substoichiometric concentrations.

Conclusions:

• PHICS represents a novel "event-driven" therapeutic modality for controlling hyperactive enzymes.
• This approach offers an alternative to traditional "occupancy-driven" drugs, overcoming resistance.
• The findings lay the groundwork for developing electric-field and event-driven therapies with orthogonal resistance profiles.