Table 2.

Notable differences between SMIs and PROTACs.

Parameter	SMIs	PROTACs
Druggability	Only limited targets are druggable	Extended scope for druggable targets
Selectivity	Lack of selectivity	Highly selective
Dosage	Require high dose; thus they are less potent	Minimal dose and highly protein
MOA	Competitive active site inhibition	Proteasomal degradation of target protein
Drug–target interactions	Usually they are non-covalent and require numerous interactions for good activity Require active site binding	POI requires minimal interactions and E3 ligase requires strong interactions for good activity No need for active site binding
Lipinski RO5	Most of them obeys RO5	Most of the PROTACs do not obey Lipinski rules
Synthetic feasibility	Usually easy to synthesize	Usually strenuous to synthesize

MOA—mechanism of action; POI—protein of interest; Ro5—rule of 5.