Table 1.

Clinically relevant advantages and limitations of PROTAC degraders compared to small molecule inhibitors

Features	PROTAC degraders	Small molecule inhibitors
Pharmacodynamic profile	Active in inhibitor-resistant cancer models [4, 44]	Acquired resistance is common [1, 44]
Selectivity	More selective and less off-target toxicity [3, 5, 45–47 ]	Side effects due to off-target toxicity [3]
Pharmacokinetic profile	Sustained target degradation and less frequent dosing [4]	Reversible target binding is common with frequent dosing [1]
Scope of application	Tolerate low affinity target binding for action; target protein complexes [6]	Require high affinity binding to protein target [6]
ADME	Higher molecular weight and potentially poor penetration to the cells; complex design may lead to rapid drug metabolism and excretion [4, 7]	ADME profile can be readily optimized [4]
Resistance mechanism	Complex design can be associated with multiple mechanisms of resistance [9]	Often due to point mutations at the binding pocket of protein target [4]

ADME: absorption, distribution, metabolism, and excretion