Hsc70-Recruiting Degraders Exploit Chaperone-Mediated Autophagy for Targeted Protein Degradation
- Researchers developed Hsc70-Mediated Targeting Chimeras (Hsc70TACs), bifunctional small molecules that link an Hsc70-binding ligand to a ligand for a protein of interest, directing target degradation through chaperone-mediated autophagy rather than the ubiquitin-proteasome pathway used by PROTACs.
- The approach is proposed to extend the range of degradable targets, including certain cytosolic and cell-membrane proteins, and to offer an alternative route that may help address resistance risks associated with proteasome-dependent degraders.
- Degradation activity was demonstrated across multiple protein classes, including the transcriptional regulator BRD4, the regulatory protein MDM2, and the cell-membrane immune checkpoint protein PD-L1, across diverse cellular contexts.
- A lead BRD4-directed compound, B-2, showed favorable pharmacokinetic behavior and produced robust BRD4 degradation in vivo, supporting continued development of the Hsc70TAC modality.
A degradation route that bypasses CRBN/VHL entirely is worth my attention regardless of target — CMA recruitment sidesteps the ubiquitin-proteasome toolbox, so it should be orthogonal to the resistance mechanisms (neosubstrate mutation, E3 downregulation) that kill PROTAC leads in the clinic. PD-L1 is the result I'd chase: pulling a membrane protein through chaperone-mediated autophagy via LAMP2A translocation is something UPS-based PROTACs structurally can't do. My skepticism sits with the Hsc70 arm — KFERQ-motif engagement is promiscuous by design, so selectivity and off-target chaperone-client disruption need real scrutiny before I trust the SAR. B-2's in vivo PK and clean BRD4 knockdown at least de-risks synthesis/linker chemistry enough to treat this as a platform, not just a proof of concept.