Table 2 Summary of protein degradation technologies
From: Protein degradation technology: a strategic paradigm shift in drug discovery
Degradation technology | Target range | Degradation pathway | Advantages | Potential problems | Refs. |
|---|---|---|---|---|---|
PROTAC | Intracellular protein | Proteasome pathway | Targeted degradation of undruggable proteins Specificity Acceptable oral bioavailability (such as ARV-110 and ARV-471) Clear degradation mechanism High degradation efficacy | Large molecular weight Poor oral bioavailability and other pharmacokinetic properties Limited target range Limited available E3 ligase | |
SNIPER | Intracellular proteins, cIAP1, and XIAP | Proteasome pathway | Simultaneous degradation of target protein and IAP, killing cancer cells that rely on IAP for survival High specificity Sufficient membrane permeability | Need an IAP ligand with high binding affinity The degradation mechanism of cIAP1 and XIAP by the SNIPERs is not well understood | |
HaloPROTAC | Endosomal proteins and HaloTag fusion protein | Proteasome pathway | Selectively induce target protein degradation; Improved drug-like properties | The stoichiometric ratio of the chemical components to the protein needs to be labeled The ability to knock the degradation label into the target protein needs to be improved The Halo label itself may become the main target of ubiquitination and degradation | |
HyT | Druggable or non-druggable proteins | Proteasome pathway | Some hydrophobic tags are independent of E3 ligases and ubiquitination Wide range of potential targets Universality | High affinity for the target protein ligand The exact mechanism of action remains unclear Potential perturbation of the unfolded protein response pathway may cause off-target effects | |
LYTAC | Extracellular and membrane-associated proteins | Endosome/lysosome pathway | Degradation does not depend on the UPS system Degrade extra-membrane and membrane-related proteins High controllability | Relative molecular mass is too large There are few types of applicable shuttle receptors Antibody may induce immune response Non-catalytic, low degradation efficiency | |
AUTAC | Intracellular proteins and damaged organelles | Selective autophagy pathway | A wide range of potential targets, including damaged organelles such as mitochondria; Proteasome-independent | Lack key information such as the specific molecular mechanism of K63 ubiquitination that mediates S-guanylation to trigger autophagy, as well as its efficiency and potential off-target effects Possible influence on selective autophagy | |
ATTEC | Cytoplasmic proteins and non-protein autophagy substrates | Macro-autophagy pathway | The relatively low molecular mass enables it to penetrate the blood–brain barrier A wide range of potential targets Mechanism of direct degradation | Lack of research on designing chimeras Urgent need to clarify the chemical structure of the compound-protein interface | |
RIBOTAC | RNA | Ribonuclease pathway | It can degrade RNA at a low concentration | Difficulties in finding small molecules that can selectively bind to the target RNA | [125] |