The HSP90-dependent bioorthogonal PROTAC prodrug system enables tumor-selective and enhanced protein degradation

  • J Control Release. 2026 May 10:393:114828. doi: 10.1016/j.jconrel.2026.114828.
Fangkui Yin  1 ,  Ting Song  2 ,  Yang Song  3 ,  Ke Wang  2 ,  Hong Zhang  3 ,  Maojun Jiang  1 ,  Zihan Wang  1 ,  Xiuwen Fan  2 ,  Yanxin Zhang  4 ,  Siyao Wang  1 ,  Yi Teng  1 ,  Haoxin Lun  1 ,  Sen Wang  2 ,  Anlai Xie  2 ,  Ziqian Wang  5 ,  Zhichao Zhang  6
Affiliations
  • 1. Cancer Hospital of Dalian University of Technology, School of Chemistry, Dalian University of Technology, Dalian, Liaoning, China 116024.
  • 2. Cancer Hospital of Dalian University of Technology, School of Pharmacy, Faculty of Medicine, Dalian University of Technology, Dalian, Liaoning, China 116024.
  • 3. Central Hospital of Dalian University of Technology, Dalian University of Technology, Dalian, Liaoning, China 116024.
  • 4. School of Life Science and Technology, Dalian University of Technology, Dalian, Liaoning, China 116024.
  • 5. Cancer Hospital of Dalian University of Technology, School of Pharmacy, Faculty of Medicine, Dalian University of Technology, Dalian, Liaoning, China 116024. Electronic address: [email protected].
  • 6. Cancer Hospital of Dalian University of Technology, School of Pharmacy, Faculty of Medicine, Dalian University of Technology, Dalian, Liaoning, China 116024. Electronic address: [email protected].
PMID: 41839264 DOI: 10.1016/j.jconrel.2026.114828
Abstract

Proteolysis targeting chimeras (PROTACs) possess significant therapeutic potential; however, they encounter challenges related to a lack of tumor specificity and normal-tissue toxicity. We developed a heat shock protein 90 (HSP90)-dependent bioorthogonal PROTAC prodrug system (HBPROTAC) to achieve tumor-specific target proteolysis. The HBPROTAC system consists of two components: (1) Tz-PU, a tetrazine-conjugated HSP90 Inhibitor designed for tumor-selective accumulation, and (2) TCO-caged PROTAC prodrugs (TCO-MZ1 or TCO-DT2216), which release active PROTACs (MZ1 or DT2216) through inverse electron demand Diels-Alder (IEDDA) reactions with Tz-PU. We demonstrated that HBPROTAC exhibited tumor-specific activation and degradation of BRD4 and Bcl-xL. Moreover, inhibition by Tz-PU synergistically enhanced the degradation efficiency of the target proteins through HSP90-mediated signaling. The tumor-specific and enhanced degradation character of HBPROTAC was confirmed in various tumor cell lines and the melanoma mouse model, demonstrating that this strategy establishes a broadly applicable platform for tumor-specific spatiotemporal control of targeted protein degradation and diminished off-tissue on-target toxicity.

Keywords
Bioorthogonal; Enhanced protein degradation; HSP90; PROTACs; Prodrug.
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