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

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 <b>Hsp70TAC</b>, 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, <b>Hsp70TACs</b> 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, <b>Hsp70TACs</b> 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, <b>Hsp70TACs</b> 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.