The binding and tagging of specific protein targets for degradation is a key area of medicinal chemistry and drug development that has become increasingly important as our knowledge of protein/ligand interactions improves. There are several different currently developed routes to targeted protein degradation, mainly through molecular glues, hydrophobic tagging of the target, and heterobifunctional proteolysis targeting chimeras. However, these strategies can only target intracellular proteins. About 40% of proteins in the proteome are outside the cells and many of them are associated with various diseases such as cancer. Lysosome targeting degraders are heterobifunctional molecules that contain a ligand for the protein target to be degraded and a ligand for cell internalization to a lysosomal compartment, which can complement existing strategies for intracellular proteins. One such target for cell internalization is the Mannose-6-Phosphate Receptor (M6PR). Current synthesis of the ligands for M6PR depend on large multivalences in Mannose-6-phosphate (M6P) that require long synthetic paths and are not optimized in their cell internalization. Our goal was to improve upon the synthesis of these lysosome targeting chimeras, and to probe the more exact binding requirements between M6P and its receptor. Our synthetic route for LYTACs streamlines those previously explored for M6P based lysosome targeting degraders and protein degradation studies have shown effective degradation of target proteins at sub micromolar concentrations of the chimera, which validates the refined models.

Synthesis of mannose-6-phosphonate conjugate for targeted protein degradation through the lysosome

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ACS Fall 2022

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