MATRACs / Membrane Anchoring Trafficking Chimeras

Targeted protein degradation by hijacking endogenous pathways with chimeric molecules is currently revolutionizing the drug oncology field. Very recently, the innovative LYTAC concept showed for the first time the ability to induce degradation of therapeutically relevant proteins located on the surface of cancer cells. The initially reported LYTAC design is a rather ill-defined large hybrid protein-synthetic polymer construct and does not allow for tumor-selective protein degradation. In our project we aim to design Membrane Anchoring TRAfficking Chimeras (MATRACs), which are chimeric molecules, composed of (1) a ligand binding to a target protein of interest for degradation (POID), whose removal from the cell surface in the TME would be of therapeutic relevance, and (2) a ligand that, in response to the acidic pH in the TME, anchors to the phospholipid cell membrane and subsequently mediates lysosomal trafficking and lysosomal degradation of the target protein of interest.