TABLE 2.

Comparison of small molecule ATP-competitive catalytic inhibitors versus PROTACs

Small Molecule ATP-Competitive Catalytic Inhibitors	PROTACs
• Target activity-dependent mechanisms of tumorigenesis.	• Target activity-dependent and -independent mechanisms of tumorigenesis for enzymatic targets. Generally higher efficacy than sole inhibition.
• Occupancy-driven mechanism of action; work at stochiometric doses.	• Catalytic mechanism of action; can work at substochiometric doses.
• Require continuous exposure for therapeutic efficacy.	• Do not require continuous exposure to achieve the desired therapeutic effect.
• Binding to the protein’s active site required.	• Binding to the active site not required; can target undruggable proteome.
• Specificity depends on binding to the target.	• Specificity of degradation also depends on recruited E3 ligase and linker composition; highly specific.
• Drug resistance easily develops.	• Potential to target drug-resistant variants and to delay the emergence of therapeutic resistance.
• Good pharmacological properties of small molecule ATP-competitive inhibitors.	• Pharmacological properties can be poor due to properties such as the size of the compounds and limited membrane permeability.