Proteolysis-targeting chimeras (PROTACs) and molecular glues have pioneered the targeted protein degradation (TPD) field and entered clinical evaluation. These small molecules utilize the ubiquitin-proteasome system to mediate intracellular protein degradation. In recent years, a new class of bifunctional degraders-including LYTACs, AbTACs, PROTABs, KineTACs, REULR, and Trim-Away-has expanded TPD strategies to target membrane and extracellular proteins, unlocking new therapeutic possibilities.
1. LYTACs (Lysosome Targeting Chimeras)
Reference: Nature 2020, 584, 291-297
LYTACs harness endogenous lysosome trafficking pathways via cation-independent mannose-6-phosphate receptors (CI-M6PR). These chimeras are composed of a targeting moiety (e.g., an antibody or small molecule) linked to a mannose-6-phosphate (M6Pn) ligand. By bridging target proteins with CI-M6PR, LYTACs mediate lysosomal degradation of extracellular and membrane proteins.
While CI-M6PR is widely expressed, other lysosome-shuttling receptors display tissue-specific patterns, offering opportunities for selective tissue targeting and improved therapeutic windows in future LYTAC applications.
2. ASGPR-LYTAC
Reference: Nat. Chem. Biol. 2021, 17, 937-946
ASGPR-LYTACs leverage the liver-specific asialoglycoprotein receptor (ASGPR) to selectively degrade extracellular proteins in hepatocytes. These LYTACs utilize GalNAc or galactose ligands that bind ASGPR and undergo clathrin-mediated endocytosis. Upon endosomal acidification, ASGPR recycles while the ligand-bound protein is trafficked to the lysosome for degradation-enabling cell-type-specific TPD.
3. KineTACs (Cytokine Receptor-Targeting Chimeras)
Reference: Nat. Biotechnol. 2023, 41, 273-281
KineTACs are fully genetically encoded bifunctional antibodies that couple a cytokine-binding arm with a target-binding arm. For example, KineTACs incorporating CXCL12 can exploit the decoy receptor CXCR7 to deliver diverse protein targets to lysosomes. Other examples involve CXCL11, vMIPII, or IL-2 for targeting respective cytokine receptors. This modular and versatile platform enables lysosomal degradation of membrane and extracellular proteins, with both broad and tissue-specific applications.
4. AbTACs (Antibody-Based TPD)
Reference: J. Am. Chem. Soc. 2021, 143, 593–598
AbTACs are bispecific recombinant antibodies designed to degrade membrane proteins via recruitment of membrane-bound E3 ligases. For instance, AbTACs targeting RNF43-a membrane-anchored E3 ligase-can mediate lysosomal degradation of PD-L1. This approach introduces an antibody-based molecular architecture for selective degradation of surface proteins, expanding the capabilities of TPD beyond small molecules.
5. PROTABs (Protein-Targeting Antibodies for Degradation)
Reference: Nature 2022, 610, 182-189
PROTABs induce degradation by tethering transmembrane E3 ligases to membrane protein targets. Using ZNRF3, a Wnt-related E3 ligase, PROTABs demonstrated potent and specific degradation of colorectal cancer targets both in vitro and in vivo. This antibody-driven strategy opens a new path for therapeutic degradation of membrane proteins with disease specificity.
6. REULR (Receptor Elimination by Ubiquitin Ligase Recruitment)
Reference: ACS Synth. Biol. 2023, 12, 1081-1093
REULRs are nanobody-based bifunctional tools that promote membrane receptor degradation via proximity-induced recruitment of transmembrane E3 ligases (e.g., RNF43, ZNRF3). They effectively eliminate disease-related receptors such as EGFR, EPOR, and PD-1. Additionally, “fratricide” REULRs have been designed to self-degrade surface E3 ligases-offering precise modulation of receptor signaling intensities in various cell types.
7. Trim-Away
Reference: Cell 2017, 171(7), 1692−1706
Trim-Away enables rapid degradation of endogenous proteins without genetic modification. This method uses antibodies to bind the target protein and TRIM21, an E3 ubiquitin ligase, to trigger proteasomal degradation. Trim-Away is ideal for primary or non-dividing cells, providing immediate effects without long-term compensation seen with RNAi or gene knockouts. It is particularly useful for studying protein function and cell signaling in hard-to-transfect systems.