Extracellular HSP90-Facilitated Degradation of Extracellular and Membrane Proteins by Bifunctional Small Molecules

Lysosome-targeting
chimeras represent a promising strategy for
degrading extracellular and membrane proteins via the lysosomal pathway,
but the available receptor options remain limited. Herein, we report
a novel strategy utilizing extracellular heat shock protein 90 (eHSP90)
to facilitate lysosomal degradation of target proteins through bifunctional
small molecules, termed extracellular heat shock protein 90-targeting
chimeras (eHSPTACs). By connecting an HSP90 ligand to a target protein
ligand, eHSPTACs effectively induced the internalization and subsequent
lysosomal degradation of extracellular Alexa Fluor 488-labeled α-DNP
antibody and membrane programmed cell death-ligand 1 (PD-L1). Notably, dPDL1-4 selectively degraded membrane PD-L1 in tumor cells
over normal cells, leveraging the elevated expression of eHSP90 in
cancer cells. Moreover, dPDL1-4 demonstrated robust in
vivo degradation of membrane PD-L1 and significant tumor growth suppression
in the B16F10 syngeneic mouse model. Overall, eHSPTACs offer a general
platform for tumor-selective degradation of extracellular and membrane
proteins, providing a new therapeutic avenue.