Journal: Nature
This study investigates kinase inhibitor-induced degradation, a process where small-molecule inhibitors not only block kinase activity but also promote their destabilization and degradation.
By profiling 98 kinases with 1,570 inhibitors, the authors identified 160 selective cases of inhibitor-driven kinase destabilization.
Kinases susceptible to degradation often overlap with HSP90 client proteins, implicating chaperone deprivation in this process.
Focused analyses on LYN, BLK, and RIPK2 kinases revealed that inhibitors induce a conformational or functional kinase state that enhances clearance via endogenous degradation pathways.
These effects may arise from changes in kinase activity, localization, or complex formation following inhibitor binding or network influences.
Overall, inhibitor-induced kinase degradation is common and suggests that amplifying natural cellular degradation mechanisms could be a viable alternative to conventional targeted protein degraders like PROTACs.