PROTACpedia
Development of small-molecule BRD4 degraders based on pyrrolopyridone derivative. Bioorg Chem. 2020 Jun;99:103817. PMID:32361153 DOI:10.1016/j.bioorg.2020.103817
Target: BRD4 Bromodomain-containing protein 4 O60885 Homo sapiens
E3 ligase: Cereblon
E3 binder: Lenalidomide
SMILES: show
Nc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O

 Ligand Name: ABBV-075
PDB with Ligand: 5UVX
IC50: = 2.5 nM
EC50 (cells): = 1.216 μM
SMILES: show
CCS(=O)(NC1=CC=C(C(C2=CN(C(C3=C2C=CN3)=O)C)=C1)OC4=CC=C(C=C4F)F)=O

Calculated Values
MW: 926.92
Hbond donors: 5
Hbond acceptors: 14
cLogP: 3.30
TPSA: 257.81

SMILES: show
O=C(C(N1)=CC(C(C2=CC(NS(=O)(CC)=O)=CC=C2OC3=CC=C(F)C=C3F)=CN4C)=C1C4=O)NCC5=CN(CCOCC(NC6=CC=CC7=C6CN(C(CC8)C(NC8=O)=O)C7=O)=O)N=N5

Linker type: PEG
Incubation time (hours): 1, 2, 3, 4, 8, 24, 48
Cells: BxPC3, DLD-1, HCT-116, MDA-MB-231, A549, PC-9
IC50: = 2.7 nM
EC50 (cells): = 0.165 μM
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?: No
Comments: Above EC50 was obtained in BxPC3 cells. EC50 for DLD-1/HCT-116/MDA-MB-231/A549/PC-9 cells: 4.09μM/6.47μM/>10μM/2.42μM/>10μM, respectively.
Contributed by: Yangwode Jing
Calculated Values
MW: 970.97
Hbond donors: 5
Hbond acceptors: 15
cLogP: 3.32
TPSA: 267.04

SMILES: show
O=C(C(N1)=CC(C(C2=CC(NS(=O)(CC)=O)=CC=C2OC3=CC=C(F)C=C3F)=CN4C)=C1C4=O)NCC5=CN(CCOCCOCC(NC6=CC=CC7=C6CN(C(CC8)C(NC8=O)=O)C7=O)=O)N=N5

Linker type: PEG
Incubation time (hours): 24, 48
Cells: BxPC3, DLD-1, HCT-116, MDA-MB-231, A549, PC-9
IC50: = 3.4 nM
EC50 (cells): = 0.245 μM
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?: No
Comments: Above EC50 was obtained in BxPC3 cells. EC50 for DLD-1/HCT-116/MDA-MB-231/A549/PC-9 cells: 5.96μM/2.22μM/>10μM/0.39μM/>10μM, respectively.
Contributed by: Yangwode Jing
Calculated Values
MW: 1,015.02
Hbond donors: 5
Hbond acceptors: 16
cLogP: 3.34
TPSA: 276.27

SMILES: show
O=C(C(N1)=CC(C(C2=CC(NS(=O)(CC)=O)=CC=C2OC3=CC=C(F)C=C3F)=CN4C)=C1C4=O)NCC5=CN(CCOCCOCCOCC(NC6=CC=CC7=C6CN(C(CC8)C(NC8=O)=O)C7=O)=O)N=N5

Linker type: PEG
Incubation time (hours): 24
Cells: BxPC3, DLD-1, HCT-116, MDA-MB-231, A549, PC-9
IC50: = 3.7 nM
EC50 (cells): = 4.138 μM
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?: No
Comments: Above EC50 was obtained in BxPC3 cells. EC50 for DLD-1/HCT-116/MDA-MB-231/A549/PC-9 cells: 2.04μM/4.39μM/>10μM/0.30μM/>10μM, respectively.
Contributed by: Yangwode Jing
Calculated Values
MW: 1,059.07
Hbond donors: 5
Hbond acceptors: 17
cLogP: 3.35
TPSA: 285.50

SMILES: show
O=C(C(N1)=CC(C(C2=CC(NS(=O)(CC)=O)=CC=C2OC3=CC=C(F)C=C3F)=CN4C)=C1C4=O)NCC5=CN(CCOCCOCCOCCOCC(NC6=CC=CC7=C6CN(C(CC8)C(NC8=O)=O)C7=O)=O)N=N5

Linker type: PEG
Incubation time (hours): 24
Cells: BxPC3, DLD-1, HCT-116, MDA-MB-231, A549, PC-9
IC50: = 12.0 nM
EC50 (cells): > 10 μM
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?: No
Comments: Above EC50 was obtained in BxPC3 cells. EC50 for DLD-1/HCT-116/MDA-MB-231/A549/PC-9 cells: >10μM/>10μM/>10μM/2.14μM/>10μM, respectively.
Contributed by: Yangwode Jing