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

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

  • J Med Chem. 2024 Sep 26;67(18):16712-16736. doi: 10.1021/acs.jmedchem.4c01518.
Jinyun Dong 1 2,  Furong Ma 3,  Maohua Cai 3,  Fei Cao 4,  Haobin Li 3,  Hui Liang 3,  Yulong Li 3,  Guangyu Ding 1 2,  Juan Li 1,  Xiangdong Cheng 1 2,  Jiang-Jiang Qin 1 2
Affiliations

Affiliations

  • 1 Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310022, China.
  • 2 Key Laboratory of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province, Hangzhou 310022, China.
  • 3 School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China.
  • 4 College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou 310032, China.
PMID: 39230973 DOI: 10.1021/acs.jmedchem.4c01518
Abstract

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.

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