Degradation of HP is initiated when PROTACs promote the HP and E3 ligase to form a ternary complex.
Subsequent HP ubiquitination at the e-amino function of a suitably exposed lysine residue can occur when the ubiquitination machinery is brought in close proximity and then the ubiquitinated HP is recognized and degraded by the 26S proteasome, which is part of the ubiquitin-proteasome system in eukaryotic cells.
As such, PROTACs disrupt specific protein functions by degrading the target proteins in a catalytic fashion instead of relying on target protein inhibition, being more efficacious and providing more sensitivity to drug-resistant targets. PROTACs have been proven to show better selectivity compared to classic inhibitors.
The PROTAC concept potentially could bring about a revolution in drug discovery and the field is expanding rapidly. Over 4000 PROTACS have been reported. At present, 15 PROTACs are in clinical development.