PROTACpedia
Targeting the C481S Ibrutinib-Resistance Mutation in Bruton's Tyrosine Kinase Using PROTAC-Mediated Degradation. Biochemistry. 2018 Jul 3;57(26):3564-3575. PMID:29851337 DOI:10.1021/acs.biochem.8b00391
Target: BTK Tyrosine-protein kinase BTK Q06187 Homo sapiens
E3 ligase: Cereblon
E3 binder: Pomalidomide
SMILES: show
Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O

 Ligand Name: Ibrutinib
Ligand PDB Id: "8E8"
PDB with Ligand: 5P9J
IC50: < 51.0 nM
SMILES: show
C=CC(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1

Calculated Values
MW: 787.83
Hbond donors: 3
Hbond acceptors: 14
cLogP: 3.58
TPSA: 213.20

SMILES: show
Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CCN(CCOCCOCC(=O)Nc2ccc3c(c2)C(=O)N(C2CCC(=O)NC2=O)C3=O)CC1

Linker type: PEG
Incubation time (hours): 1,2,4,8,16,24
Cells: NAMALWA, XLA
IC50: < 46.9 nM
DC50: < 14.9 nM
Dmax: > 99 %
Tested a non-binding E3 control?: Yes
Tested competition with ligand?: Yes
Tested proteaseome inhibitor?: Yes
Proteomics data available?: Yes
Tested engagement in cells?: Yes
Off-targets reported?: Significant binding to: TEC, ERBB2, ERBB3, HCK, YES, BRK, LCK, BLK, CSK, RIPK2, MEK5, CSNK1E
Comments: DC50 is 9.1 nM (WT BTK, NAMALWA cells), 14.6 nM (WT BTK, XLA cells), 14.9 nM (C481S, XLA cells). IC50 of PROTAC is 46.9 (WT BTK), 20.9 (C481S). IC50 of ligand is 51.0 nM (WT BTK), 30.7 (C481S)
Contributed by: Barr Tivon
Calculated Values
MW: 829.92
Hbond donors: 3
Hbond acceptors: 14
cLogP: 4.75
TPSA: 213.20

SMILES: show
Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CCN(CCCOCCCOCCC(=O)Nc2cccc3c2C(=O)N(C2CCC(=O)NC2=O)C3=O)CC1

Linker type: non-PEG polyether
Cells: NAMALWA
DC50: = 68.3 nM
Dmax: = 95 %
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: IC50 of ligand is 51.0 nM (WT BTK), 30.7 (C481S)
Contributed by: Barr Tivon
Calculated Values
MW: 843.94
Hbond donors: 3
Hbond acceptors: 14
cLogP: 5.14
TPSA: 213.20

SMILES: show
Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CCN(CCCCOCCCCOCC(=O)Nc2cccc3c2C(=O)N(C2CCC(=O)NC2=O)C3=O)CC1

Linker type: non-PEG polyether
Cells: NAMALWA
DC50: = 90.1 nM
Dmax: = 93 %
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: IC50 of ligand is 51.0 nM (WT BTK), 30.7 (C481S)
Contributed by: Barr Tivon
Calculated Values
MW: 843.94
Hbond donors: 3
Hbond acceptors: 14
cLogP: 5.14
TPSA: 213.20

SMILES: show
Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CCN(CCCCCCOCCOCC(=O)Nc2cccc3c2C(=O)N(C2CCC(=O)NC2=O)C3=O)CC1

Linker type: non-PEG polyether
Cells: NAMALWA
DC50: = 80.6 nM
Dmax: = 96 %
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: IC50 of ligand is 51.0 nM (WT BTK), 30.7 (C481S)
Contributed by: Barr Tivon
Calculated Values
MW: 843.94
Hbond donors: 3
Hbond acceptors: 14
cLogP: 5.14
TPSA: 213.20

SMILES: show
Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CCN(CCCCOCCCCOCC(=O)Nc2ccc3c(c2)C(=O)N(C2CCC(=O)NC2=O)C3=O)CC1

Linker type: non-PEG polyether
Cells: NAMALWA
DC50: = 11.6 nM
Dmax: > 99 %
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: IC50 of ligand is 51.0 nM (WT BTK), 30.7 (C481S)
Contributed by: Barr Tivon
Calculated Values
MW: 787.83
Hbond donors: 3
Hbond acceptors: 14
cLogP: 3.58
TPSA: 213.20

SMILES: show
Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CCN(CCOCCOCC(=O)Nc2cccc3c2C(=O)N(C2CCC(=O)NC2=O)C3=O)CC1

Linker type: PEG
Cells: NAMALWA
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: IC50 of ligand is 51.0 nM (WT BTK), 30.7 (C481S)
Contributed by: Barr Tivon
Calculated Values
MW: 743.78
Hbond donors: 3
Hbond acceptors: 13
cLogP: 3.56
TPSA: 203.97

SMILES: show
Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CCN(CCOCC(=O)Nc2cccc3c2C(=O)N(C2CCC(=O)NC2=O)C3=O)CC1

Linker type: PEG
Cells: NAMALWA
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: IC50 of ligand is 51.0 nM (WT BTK), 30.7 (C481S)
Contributed by: Barr Tivon