Perspectives on the Development of First-in-Class Protein Degraders

Abstract

Targeted protein degradation is a broad and expanding field aimed at the modulation of protein homeostasis. A focus of this field has been directed toward molecules that hijack the ubiquitin proteasome system with heterobifunctional ligands that recruit a target protein to an E3 ligase to facilitate polyubiquitination and subsequent degradation by the 26S proteasome. Despite the success of these chimeras toward a number of clinically relevant targets, the ultimate breadth and scope of this approach remains uncertain. Here we highlight recent advances in assays and tools available to evaluate targeted protein degradation, including and beyond the study of E3-targeted chimeric ligands. We note several challenges associated with degrader development and discuss various approaches to expanding the protein homeostasis toolbox.

Beyond canonical PROTAC: biological targeted protein degradation (bioTPD)

“…In recent years, TPD methods that use the lysosomal degradation pathway, such as antibody-based PROTAC (AbTAC), lysosome-targeting chimeras (LYTAC), GlueTAC, bispecific aptamer chimeras, AUtophagy-targeting chimeras (AUTAC) or, AUTOphagy-targeting chimeras (AUTOTAC), and autophagy-tethering compounds (ATTEC) have emerged [ 10 , 45 ]. Endosome-lysosome and autophagy-lysosome are two lysosomal degradation pathways commonly involved in TPD.…”

“…Biological TPD (bioTPD), which includes the previously mentioned peptide-based PROTAC and other non-small molecule-based TPD technologies constituted of nucleic acids, or proteins [ 10 , 45 , 94 ], exhibits numerous advantages over small-molecule TPD. These include: (1) antibodies and peptides can specifically bind undruggable proteins and are not affected by the target protein binding pocket, which is more conducive to the construction of bioTPD [ 95 ]; (2) protein- and peptide-based bioTPD are less demanding to design and synthesize and display superior safety and less toxicity [ 96 ]; (3) the ligands of protein/peptides can recognize the mutated target [ 97 ], thus reducing off-target effects; (4) LYTAC, GlueTAC, nucleic acid PROTAC, and other TPDs that depend on the lysosomal pathway can degrade membrane proteins and extracellular proteins [ 10 ]; and (5) The ligand affinity and specificity of peptide or antibody (antibody fragments) is usually higher than that of small-molecule compounds, which may contribute to higher efficiency and selectivity of bioTPD.…”

“…With the preliminary success of CI-MPR- and ASGPR-based LYTAC, it will be promising to exploit other cell-specific and tissue-specific LTRs [ 10 ]. Importantly, it is worth noting that current LYTACs are degraded along with POIs, which suggests a lack of desirable catalytic function compared with most PROTAC degraders [ 45 ]. In addition, the large molecular weights of the antibodies and immune responses induced by the conjugated glycopeptide should be addressed.…”