Structure-Based Design of a Macrocyclic PROTAC. Angew Chem Int Ed Engl. 2019 Nov 19. PMID:31746102 DOI:10.1002/anie.201914396
Target: BRD4 Bromodomain-containing protein 4 O60885 Homo sapiens
E3 ligase: VHL
E3 binder: Vh032
SMILES: show
Cc1ncsc1-c1ccc(CNC(=O)[C@@H]2C[C@@H](O)CN2C(=O)[C@@H](N)C(C)(C)C)cc1

Ligand Name: JQ1
Ligand PDB Id: JQ1
PDB with Ligand: 3MXF
SMILES: show
Cc1sc2c(c1C)C(c1ccc(Cl)cc1)=N[C@@H](CC(=O)OC(C)(C)C)c1nnc(C)n1-2

Calculated Values
MW: 1,118.78
Hbond donors: 4
Hbond acceptors: 18
cLogP: 5.39
TPSA: 239.18

SMILES: show
Cc1ncsc1-c1ccc2c(c1)OCCOCCOC[C@@H](NC(=O)C[C@@H]1N=C(c3ccc(Cl)cc3)c3c(sc(C)c3C)-n3c(C)nnc31)COCCOCCOCC(=O)N[C@@H](C(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)NC2

Linker type: Other
Incubation time (hours): 4,18
Cells: hela
IC50: = 189 nM
DC50: < 125 nM
Dmax: = 90 %
Tested a non-binding E3 control?: No
Tested competition with ligand?: No
Tested proteaseome inhibitor?: No
Proteomics data available?: No
Tested engagement in cells?: No
Off-targets reported?: Brd2 and Brd3 (DC50 >125nM)
Comments: they heva a ternary complex crystal structure but dont give PDB. DC50 is between 25-125nM
Contributed by: Efrat Resnick