2. Academic Validation
  3. Hsp70-Targeting Chimeras Enable Dual Proteasomal and Lysosomal Degradation of Intracellular and Extracellular Proteins

Hsp70-Targeting Chimeras Enable Dual Proteasomal and Lysosomal Degradation of Intracellular and Extracellular Proteins

  • J Med Chem. 2026 Apr 9;69(7):8417-8432. doi: 10.1021/acs.jmedchem.5c03784.
Zihan Wang 1,  Pengfei Li 2,  Fangkui Yin 1,  Hong Zhang 3,  Siyao Wang 1,  Yi Teng 1,  Xiuwen Fan 4,  Ke Wang 4,  Yanxin Zhang 5,  Haoxin Lun 1,  Ting Song 4,  Ziqian Wang 4,  Zhichao Zhang 4
Affiliations

Affiliations

  • 1 Cancer Hospital of Dalian University of Technology, School of Chemistry, Dalian University of Technology, Dalian, Liaoning 116024, China.
  • 2 Department of Thoracic Surgery, Cancer Hospital of Dalian University of Technology, Liaoning Cancer Hospital & Institute, Shenyang, Liaoning 110042, China.
  • 3 Central Hospital of Dalian University of Technology, Dalian University of Technology, Dalian, Liaoning 116024, China.
  • 4 Cancer Hospital of Dalian University of Technology, School of Pharmacy, Faculty of Medicine, Dalian University of Technology, Dalian, Liaoning 116024, China.
  • 5 School of Life Science and Technology, Dalian University of Technology, Dalian, Liaoning 116024, China.
PMID: 41874277 DOI: 10.1021/acs.jmedchem.5c03784
Abstract

Developing targeted protein degradation (TPD) strategies with disease-specific mechanisms, modularity, and facile designability could ensure drug efficacy and selectivity. Herein, a small-molecule, Hsp70-based targeted protein degradation platform, termed Hsp70TAC, is described that enables tumor-selective degradation of both intracellular and extracellular proteins through distinct cellular pathways. By conjugating protein-of-interest (POI) ligands to HSP70 inhibitors, Hsp70TACs exploits the chaperone functions of HSP70 to enable protein degradation through both the ubiquitin-proteasome system and the endocytosis-lysosome pathway. As a proof of concept, Hsp70TACs induced efficient degradation of intracellular Bromodomain Protein 4 (BRD4) via the ubiquitin-proteasome system (DC50 = 0.67 μM) and membrane-bound Programmed Death Ligand 1 (PD-L1) via caveolin-mediated endocytosis-lysosomal processing (DC50 = 0.84 μM). Moreover, Hsp70TACs exploits the elevated expression of HSP70 in tumor cells to preferentially accumulate in these cells, thereby enabling the tumor-selective degradation of POIs in Hsp70-enriched tumor cells.

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