Targeted Protein Degradation(TPD)
Limitation of Current TPD Modalities
1) Molecular Gule : It has a small molecular weight, resulting in good drug-like properties, but it cannot be designed to target specific targets. It can only utilize the proteasome, making it difficult to target aggregated proteins or membrane proteins.
2) PROTAC : It is a structure in which an E3 ligase-binding molecule and a target protein-binding molecule are linked via a linker, which increases molecular weight and reduces drug-like properties. Since only a single type of E3 ligase is used, there is a limitation on the proteins that can be targeted, and the risk of resistance development is high. It can only utilize the proteasome, making it difficult to target aggregated proteins or membrane proteins.
While first generation TPD approaches have exhibited potential, they have also revealed challenges owing to narrow range of protein-degrading mechanisms. They use a single type of E3 ubiquitin ligase for proteasomal degradation, and are not fully effective against protein aggregates and membrane proteins. Also, there may be potential caveats associated with the use of E3 ubiquitin ligase in an exclusive manner, such as drug resistance and disturbed protein homeostasis
Targeted Protein Degradation (TPD) Technology
Human diseases are known to be caused by approximately 3,000 proteins. Existing drugs exert their effects by binding to specific regions of pathogenic proteins and inhibiting their function. TPD (Targeted Protein Degradation) technology operates differently from conventional drugs; it directs target proteins to the proteasome for degradation, thereby eliminating pathogenic proteins. By applying this technology, it becomes possible to develop drugs for "undruggable targets" that were previously difficult to approach using conventional methods.
TPD (Targeted Protein Degradation) technology has emerged as a novel therapeutic modality that harnesses intracellular proteosomal and lysosomal protein degradation pathways for selective elimination of pathological proteins. This approach enables the modulation of proteins that have been difficult to target with conventional small-molecule drugs.
TPD technology enables the drugging of targets that were previously considered undruggable.