Table 4.

E3 protein ligand, structure of the linker and POI ligand with a description of the properties research for FKBP12, E3 ligases, an enzyme, a Tau degrader and a recent non-natural fusion protein.

Table entry	E3 protein (ligand)	Linker	POI ligand	POI	Potency/efficacy	Reference
1.	CRBN (thalidomide)	n-butyl and		FKBP12	80% reduction of FKBP12 at 0.1 μM and 50% reduction at 0.01 μM in MV4-11 cells	Winter [6]
2.	VHL (9)		(9)	VHL	CM11 (n = 5) induced complete depletion of VHL after 4 h at 10 nM. Potent, long-lasting and selective degradation of VHL, with DC50 of < 100 nM	Maniaci [117]
3.	VHL (9)			DHODH	IC50 for DHODH 93 nM. No degradation observed. Linker optimization needed to target the inner mitochondrial protein.	Madak [121]
4.	Keap1 (Keap1 binding peptide)*	GSGS peptide	YQQYQDATADEQG	Tau	Poly-D-arginine was added for cell penetration. Strong in vitro binding with Keap1 and Tau. Keap1-dependent degradation by enhancing the ubiquitination of Tau.	Lu [124]
5.	CRBN (thalidomide)			FKBP12F36V Fusion proteins	Degradation of a panel of fusion chimeras with FKBP12F36V including: BRD4, HDAC1, EZH2, Myc, PLK1 and KRASG12V. Rapid degradation in vivo was shown	Nabet [33]
6.	CRBN (pomalidomide)		pomalidomide	CRBN	The homo-PROTAC with n = 2 was identified as the most potent degrader. Degradation observed at 10 nM after 16 h. Hook-effect observed at 100 μM	Steinebach [118]

The structure of the CRBN ligands and the VHL ligand (9) are shown in Fig. 2. *Keap1 binding peptide: Ac-LDPETGEYL-OH.