Lysosome-Targeting Chimeras: Design, Mechanisms, and Degradation of "Rogue" Proteins

Inhibition of proteins has been a key approach in drug development for various diseases. Many therapeutic approaches have been developed till date to effectively disrupt disease-associated proteins. However, challenges such as associated side effects, gene mutation, and limited druggability of some proteins continue to drive the search for novel and better therapeutics. Targeted Protein Degradation (TPD) has surged in popularity over the past two decades as a means to eliminate disease-causing, yet undruggable proteins. Among TPD technologies, proteolysis-targeting chimeras and molecular glues are widely studied, providing a basis for protein degradation-based therapies. However, their limitations towards certain targets, particularly cytoplasmic proteins, prompt researchers to design novel technologies. Lysosome-targeting chimeras (LYTACs) are a recent and notable addition to the TPD arsenal, and they have demonstrated excellent targeting capability against both intracellular and membrane-bound aberrant and disease-associated proteins (rogue proteins). This review delves into the design and mechanisms of action of LYTACs targeting extracellular proteins, such as apolipoprotein E4, carbonic anhydrase IX, vascular endothelial growth factor, platelet-derived growth factor, matrix metalloproteinases, and cytokine macrophage migration 36 inhibitory factor, and membrane-bound proteins, including epidermal growth factor receptor, programmed death-ligand 1, transferrin receptor 1, receptor tyrosine kinases and integrins, as well as autophagy-lysosome-induced degradation agents that rely particularly on lysosome formation. Additionally, it provides insights into the development of next-generation LYTACs to improve target specificity and reduce off-target effects. We hope this review will provide a valuable resource for researchers interested in protein degradation technologies, particularly LYTACs, and to inspire the design and synthesis of more efficient protein degraders.