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Crews and Deshaies built a two-headed molecule linking a ligand for the target protein MetAP-2 to a peptide recognised by an E3 ubiquitin ligase, and showed it induced ubiquitination and degradation of the target, founding targeted protein degradation.
The proteolysis-targeting chimera (Protac-1) joined ovalicin, which binds methionine aminopeptidase-2, to the IkappaBalpha phosphopeptide recognised by the SCF-beta-TRCP E3 ligase. In Xenopus egg extracts, Protac-1 recruited MetAP-2 to the ligase and triggered its ubiquitination and proteasomal degradation.
The paper established the principle that a bifunctional molecule can hijack the cell's own disposal machinery to eliminate a chosen protein, including proteins with no enzymatic activity to inhibit. Peptide-based PROTACs were poorly cell-permeable; the field became practical when all-small-molecule degraders using VHL and cereblon ligands appeared (Bondeson 2015; Winter 2015, dBET1 degrading BRD4 in vivo).
Degraders now include vepdegestrant (oestrogen receptor), ARV-110 and other androgen-receptor degraders, and the molecular glues (lenalidomide-class drugs) reinterpreted through the same mechanism.
Instead of blocking a cancer protein, a drug can now remove it entirely, which works even for proteins without a druggable active site and can overcome resistance driven by target overexpression or mutation. Several degraders are in late-stage trials for breast and prostate cancer.
Shares Degrader-antibody conjugate (DAC), PROTACs & molecular glues (targeted protein degradation).
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Shares Degrader-antibody conjugate (DAC), PROTACs & molecular glues (targeted protein degradation).
Shares Degrader-antibody conjugate (DAC), The undruggable drivers, PROTACs & molecular glues (targeted protein degradation).
Shares Molecular glue discovery platforms, The undruggable drivers, PROTACs & molecular glues (targeted protein degradation).
Shares Molecular glue discovery platforms, The undruggable drivers, Androgen receptor, PROTACs & molecular glues (targeted protein degradation).
Shares Vepdegestrant, PROTACs & molecular glues (targeted protein degradation).
Shares Vepdegestrant, PROTACs & molecular glues (targeted protein degradation).