Inhibitors supercharge kinase turnover through native proteolytic circuits.

Area of Science:

• Biochemistry
• Pharmacology
• Molecular Biology

Background:

• Targeted protein degradation uses molecules like PROTACs to eliminate target proteins.
• Inhibitor-induced protein destabilization is sporadically observed, especially for kinase inhibitors.
• The frequency, generalizability, and mechanisms of this phenomenon remain unclear.

Purpose of the Study:

• To investigate the frequency and mechanisms of kinase inhibitor-induced protein degradation.
• To identify kinases prone to degradation and understand the underlying molecular logic.
• To explore supercharging endogenous degradation as a therapeutic strategy.

Main Methods:

• Generated dynamic abundance profiles for 98 kinases using 1,570 kinase inhibitors.
• Analyzed cellular perturbations to identify instances of inhibitor-induced destabilization.
• Conducted detailed mechanistic studies on LYN, BLK, and RIPK2 degradation.

Main Results:

• Identified 160 selective instances of inhibitor-induced kinase destabilization.
• Found that HSP90 client kinases are frequently prone to degradation.
• Revealed a common mechanism where inhibitors induce a kinase state cleared by endogenous degradation pathways.

Conclusions:

• Inhibitor-induced kinase degradation is a common event, not limited to PROTACs or molecular glues.
• Ligand-induced changes in kinase activity, localization, or assembly can trigger degradation.
• Supercharging endogenous degradation circuits presents a viable alternative to traditional targeted protein degraders.