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About Chaperon Mediated Target Protein Degradation
TPD is an emerging new therapeutic modality with potential to tackle diseases famed as undruggable targets with conventional small molecule approaches.
PROTAC degrader has a bifunctional structure comprised of three elements- an E3 ligase ligand, a POI ligand and a linker part to connect the two ligands together.
Once they formed a proximity induced ternary complex, exposed lysine on the target protein highjacks poly-ubiquitination by the E3 ligase complex followed by UPS-mediated protein degradation.
Chaperon mediated degrader has also a bifunctional structure, however key difference of chaperon-mediated degrader compared to CRBN-PROAC, chaperon degrader is not directly bind to E3 ligase but HSP90 ATP binding site to let chaperon initiate his business to bring multiple E3 ligases close enough to target protein for poly-ubiquitination and its subsequent degradation by proteosome machinery.
Following target protein degradation, E3 ligases are free to engage another target protein and repeat UPS mediated protein degradation. In this way a single chaperon degrader molecule can destroy many copies of its target protein.
PROTAC degrader has a bifunctional structure comprised of three elements- an E3 ligase ligand, a POI ligand and a linker part to connect the two ligands together.
Once they formed a proximity induced ternary complex, exposed lysine on the target protein highjacks poly-ubiquitination by the E3 ligase complex followed by UPS-mediated protein degradation.
Chaperon mediated degrader has also a bifunctional structure, however key difference of chaperon-mediated degrader compared to CRBN-PROAC, chaperon degrader is not directly bind to E3 ligase but HSP90 ATP binding site to let chaperon initiate his business to bring multiple E3 ligases close enough to target protein for poly-ubiquitination and its subsequent degradation by proteosome machinery.
Following target protein degradation, E3 ligases are free to engage another target protein and repeat UPS mediated protein degradation. In this way a single chaperon degrader molecule can destroy many copies of its target protein.
