2. Academic Validation
  3. The HSP90-dependent bioorthogonal PROTAC prodrug system enables tumor-selective and enhanced protein degradation

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

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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