Table 2.

Comparison of the PROTAC vs empirical exploitation of E3 ligase receptors to create a template for targeted protein degradation.

PROTAC	DCAFs as templates
Requires a ligand binder for the target	Requires identification of ligand binding “hotspots” to attract neo-substrates
Linkers, E3-binding and target-binding components of the large bifunctional molecules need to be optimized	DCAF “hotspots” select for drug like properties in the ligands
Target known	Phenotypic screen defines target; Requires empirical definition of neo-substrates using proteomics or selecting targets based on degron motifs
Protein-protein interactions (ternary complexes) and E3-ligase binding “hotspots” are important	Protein-protein interactions (ternary complexes) and template ‘hotspots’ are important
Exploit known biology; molecular targeted approach	Explore new biology; targeted or poly-pharmacology
First examples reaching clinic	Clinical compounds