The first PROTAC: a chimeric molecule that tags a protein for destruction
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.
- Protac-1 induced ubiquitination and degradation of MetAP-2 in cell extracts by recruiting the SCF E3 ligase
- Degradation required both halves of the chimera and an intact ubiquitin-proteasome pathway
- Introduced the terminology and concept of proteolysis-targeting chimeras
- Small-molecule successors (2015 onwards) achieved in vivo degradation of BRD4 and other targets at nanomolar potency
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.
- The original molecule was a large peptide conjugate with no cell permeability; clinical degraders took 15 years
- Degraders are large molecules with challenging oral bioavailability and pharmacokinetics
- Ligase expression varies between tissues and tumours, and resistance via ligase loss has been documented
- Clinical superiority over inhibitors has so far been modest in the first phase 3 readouts (for example vepdegestrant)
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Shares Androgen receptor, PROTACs & molecular glues (targeted protein degradation).