Hsc70-Mediated Targeting Chimeras for Targeted Protein Degradation via Chaperone-Mediated Autophagy.

Despite the remarkable success of proteolysis-targeting chimeras (PROTACs), challenges such as limited applicability to certain cytosolic proteins, potential resistance risks, and off-target effects remain. Novel degradation strategies harnessing the autophagy/lysosome pathway may broaden the scope of protein targets and address resistance, providing a promising complement to PROTACs. Herein, the bifunctional small-molecule Hsc70-Mediated Targeting Chimeras, termed Hsc70TACs, was designed by conjugating a small molecule targeting Hsc70 with the ligands of the protein of interest (POI). We demonstrate the scope of Hsc70TACs through the degradation of therapeutically relevant proteins such as BRD4, MDM2 and even cell-membrane protein PD-L1 across diverse cellular contexts. More importantly, compound B-2, a novel BRD4 Hsc70TAC, shows favorable pharmacokinetic properties and robust in vivo BRD4 degradation, thus further highlighting the potential value of Hsc70TAC. Overall, Hsc70TAC demonstrates a new avenue to target and degrade disease-associated proteins, providing a valuable addition to current protein degradation technologies.