Fig. 1: Mechanism of action of PROteolysis-TArgeting Chimeras (PROTACs).
From: Synthesis, biological evaluation and clinical trials of Cereblon-based PROTACs
In the Ubiquitin-Proteasome System (UPS), the process of ubiquitination begins when the ubiquitin protein (Ub) is activated by the ubiquitin-activating E1 enzyme. The activated Ub is then transferred to the ubiquitin-conjugating enzyme E2. Afterwards, the E3 ubiquitin ligase connects both to the target protein and to the E2-Ub complex, enabling the attachment of ubiquitin molecules to the target. Once tagged with a polyubiquitin chain, the target protein is recognized and degraded by the 26S proteasome. PROTACs are heterobifunctional molecules containing a target protein ligand at one end, and an E3 ligase ligand capable of recruiting an E3 ligase enzyme from the UPS to the other end, with a linker establishing the connection between the two ligands. Within the cell, PROTAC promotes the simultaneous and artificial binding of the target protein to an E3 ligase, forming a stable ternary complex. This leads to the target poly-ubiquitination and subsequent non-natural degradation by the UPS.
