Target: ZFP91 E3 ubiquitin-protein ligase ZFP91 Q96JP5 Homo sapiens

E3 Ligand Binder

E3 ligase: Cereblon
E3 binder: Pomalidomide
SMILES: show

Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O

Ligand

Ligand Name: Napabucasin
SMILES: show

O=C(C1=C2C=C(C(C)=O)O1)C3=CC=CC=C3C2=O

Representative PROTAC (Active) name: XD2-149 - status:Reviewed Edit

Calculated Values
MW: 693.76
Hbond donors: 3
Hbond acceptors: 10
cLogP: 3.57
TPSA: 175.20

SMILES: show

O=C(N(C1=O)C2CCC(NC2=O)=O)C3=C1C=CC=C3NCCCCCC4CCN(CCNC(C5=CC6=C(O5)C(C7=CC=CC=C7C6=O)=O)=O)CC4

Linker type: Other
Incubation time (hours): 16, 24
Cells: Pancreatic cancer cell lines BxPC-3; MIA PaCa-2
EC₅₀ (cells): ~ 1 μM
DC₅₀: ~ 70 nM
D_max: > 90 %
Tested a non-binding E3 control?: Yes
Tested competition with ligand?: Yes
Tested proteaseome inhibitor?: Yes
Proteomics data available?: Yes
Tested engagement in cells?: No
Off-targets reported?: No

Comments: XD2-149 was initially designed to degrade STAT3. However, experiments showed that XD2-149 down-regulate STAT3 level in a proteasome-independent manner. Proteomics data revealed that an E3 ligase, ZFP91, was the true substrate for this PROTAC. This paper reported a total of 22 PROTACs, which differed from each other in linker design and E3 binder choices (pomalidomide/thalidomide/lenalidomide). However, the authors didn't mention whether the remaining 21 molecules could degrade ZFP91 or not. It is also interesting that pomalidomide itself can induce the degradation of CRBN neo-substrates like ZFP91 (DC50: 0.42μM, 5-fold less potent than XD2-149), since pomalidomide can remodel CRBN surface for binding proteins like ZFP91 (Nat Med., 2019, doi: 10.1038/s41591-019-0668-z).

Contributed by: Yangwode Jing