Although proteolysis targeting chimeras (PROTACs) have emerged as a powerful tool for targeted protein degradation, their strategy relies on the ubiquitin proteasome system, limiting their targets to proteins with accessible cytosolic domains. There is still an unmet need in addressing secreted and membrane proteins that play important roles in disease pathogenesis and progressions. We have developed lysosome targeting chimeras (LYTACs) for degrading extracellular and transmembrane proteins, including ApoE4, EGFR, CD71, and PD-L1. Our strategy takes advantage of endogenous surface receptors called the mannose-6-phosphate receptors (M6PRs) that traffic proteins to the lysosome. Our first-generation LYTAC consisted of an antibody non-specifically functionalized with heterogenous glycopolymer ligands for binding a target protein and the internalizing receptor. For the next-generation LYTAC, we are developing homogenous glycopeptide ligands for site-specific conjugations on antibodies to determine the optimal architecture of LYTAC for improved efficacy and pharmacokinetics. In addition, tissue-selectivity was challenging with our original LYTAC due to the broad tissue distribution of M6PR. To overcome this, we developed LYTACs that can target membrane proteins in a specific tissue by harnessing other internalizing receptors.

Advancing lysosomal targeting chimeras (LYTACs): Structural optimization and tissue specific protein degradation

ACS Fall 2020 Virtual Meeting

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