Heat Shock Protein 90 Interactome-Mediated Proteolysis Targeting Chimera (HIM-PROTAC) Degrading Glutathione Peroxidase 4 to Trigger Ferroptosis

Targeted protein degradation (TPD)
is an emerging therapeutic paradigm
aimed at eliminating the disease-causing protein with aberrant expression.
Herein, we report a new approach to inducing intracellular glutathione
peroxidase 4 (GPX4) protein degradation to trigger ferroptosis by
bridging the target protein to heat shock protein 90 (HSP90), termed
HSP90 interactome-mediated proteolysis targeting chimera (HIM-PROTAC).
Different series of HIM-PROTACs were synthesized and evaluated, and
two of them, GDCNF-2/GDCNF-11 potently induced ferroptosis via HSP90-mediated
ubiquitin-proteasomal degradation of GPX4 in HT-1080 cells with DC50 values of 0.18 and 0.08 μM, respectively. In particular,
GDCNF-11 showed 15-fold more ferroptosis selectivity over GPX4 inhibitor
ML162. Moreover, these two degraders effectively suppress tumor growth
in the mice model with relatively low toxicity as compared to the
combination therapy of GPX4 and HSP90 inhibitors. In general, this
study demonstrated the feasibility of degrading GPX4 via HSP90 interactome,
and thus provided a significant complement to existing TPD strategies.