PROTACpedia
Mutant-Selective Allosteric EGFR Degraders are Effective Against a Broad Range of Drug-Resistant Mutations. Angew Chem Int Ed Engl. 2020 Aug 17;59(34):14481-14489. PMID:32510788 DOI:10.1002/anie.202003500
Target: EGFR Epidermal growth factor receptor P00533 Homo sapiens
E3 ligase: Cereblon
E3 binder: Pomalidomide
SMILES: show
Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O

 Ligand Name: JBJ-07-149
IC50: = 1.1 nM
EC50 (cells): = 4.9 μM
SMILES: show
O=C(NC1=NC=CS1)C(N(CC2=C3C=C(C4=CN=C(N5CCNCC5)C=C4)C=C2)C3=O)C6=CC=CC=C6

Calculated Values
MW: 942.07
Hbond donors: 3
Hbond acceptors: 15
cLogP: 4.23
TPSA: 204.94

SMILES: show
O=C(NC1=NC=CS1)C(N(CC2=C3C=C(C4=CC=C(N5CCN(CCOCCOCCOCCNC6=CC=CC(C(N7C(CC8)C(NC8=O)=O)=O)=C6C7=O)CC5)N=C4)C=C2)C3=O)C9=CC=CC=C9

Linker type: PEG
Incubation time (hours): 0, 4, 6, 8, 24, 48, 72
Cells: Ba/F3; H1975
EC50 (cells): = 0.096 μM
Dmax: > 70 %
Tested a non-binding E3 control?: Yes
Tested competition with ligand?: Yes
Tested proteaseome inhibitor?: No
Proteomics data available?: No
Tested engagement in cells?: No
Off-targets reported?: No
Comments: EC50: 0.096μM for L858R/T790M mutant EGFR Ba/F3 cells; >10μM for wildtype EGFR Ba/F3 cells
Contributed by: Yangwode Jing
Calculated Values
MW: 943.05
Hbond donors: 2
Hbond acceptors: 15
cLogP: 4.19
TPSA: 202.14

SMILES: show
O=C(NC1=NC=CS1)C(N(CC2=C3C=C(C4=CC=C(N5CCN(CCOCCOCCOCCOC6=CC=CC(C(N7C(CC8)C(NC8=O)=O)=O)=C6C7=O)CC5)N=C4)C=C2)C3=O)C9=CC=CC=C9

Linker type: PEG
Incubation time (hours): 72
Cells: Ba/F3
EC50 (cells): = 2.07 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
Contributed by: Yangwode Jing
Calculated Values
MW: 898.02
Hbond donors: 3
Hbond acceptors: 14
cLogP: 4.21
TPSA: 195.71

SMILES: show
O=C(NC1=NC=CS1)C(N(CC2=C3C=C(C4=CC=C(N5CCN(CCOCCOCCNC6=CC7=C(C(N(C(CC8)C(NC8=O)=O)C7=O)=O)C=C6)CC5)N=C4)C=C2)C3=O)C9=CC=CC=C9

Linker type: PEG
Incubation time (hours): 72
Cells: Ba/F3
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
Contributed by: Yangwode Jing
Calculated Values
MW: 942.07
Hbond donors: 3
Hbond acceptors: 15
cLogP: 4.23
TPSA: 204.94

SMILES: show
O=C(NC1=NC=CS1)C(N(CC2=C3C=C(C4=CC=C(N5CCN(CCOCCOCCOCCNC6=CC7=C(C(N(C(CC8)C(NC8=O)=O)C7=O)=O)C=C6)CC5)N=C4)C=C2)C3=O)C9=CC=CC=C9

Linker type: PEG
Incubation time (hours): 72
Cells: Ba/F3
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
Contributed by: Yangwode Jing
E3 ligase: Cereblon
E3 binder: Pomalidomide
SMILES: show
Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O

 Ligand Name: JBJ-04-125-02
SMILES: show
O=C(NC1=NC=CS1)C(C2=CC(F)=CC=C2O)N(CC3=C4C=C(C5=CC=C(N6CCNCC6)C=C5)C=C3)C4=O

Calculated Values
MW: 975.07
Hbond donors: 4
Hbond acceptors: 15
cLogP: 4.68
TPSA: 212.28

SMILES: show
O=C(NC1=NC=CS1)C(N(CC2=C3C=C(C4=CC=C(N5CCN(CCOCCOCCOCCNC6=CC=CC(C(N7C(CC8)C(NC8=O)=O)=O)=C6C7=O)CC5)C=C4)C=C2)C3=O)C9=CC(F)=CC=C9O

Linker type: PEG
Incubation time (hours): 6, 24, 48, 72
Cells: Ba/F3
IC50: = 19 nM
EC50 (cells): = 0.477 μM
Tested a non-binding E3 control?: Yes
Tested competition with ligand?: No
Tested proteaseome inhibitor?: No
Proteomics data available?: No
Tested engagement in cells?: No
Off-targets reported?: No
Comments: Targeting EGFR L858R/T790M mutant
Contributed by: Yangwode Jing
E3 ligase: Cereblon
E3 binder: Pomalidomide
SMILES: show
Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O

 Ligand Name: JBJ-04-125-02 analogue
SMILES: show
O=C(NC1=NC=CS1)C(N(CC2=C3C=C(C4=CC=C(N5CCNCC5)C=C4)C=C2)C3=O)C6=CC(F)=CC=C6F

Calculated Values
MW: 977.06
Hbond donors: 3
Hbond acceptors: 14
cLogP: 5.11
TPSA: 192.05

SMILES: show
O=C(NC1=NC=CS1)C(C2=CC(F)=CC=C2F)N(CC3=C4C=C(C5=CC=C(N6CCN(CCOCCOCCOCCNC7=CC=CC(C(N8C(CC9)C(NC9=O)=O)=O)=C7C8=O)CC6)C=C5)C=C3)C4=O

Linker type: PEG
Incubation time (hours): 6, 24, 48, 72
Cells: Ba/F3
IC50: = 390 nM
EC50 (cells): = 0.153 μM
Tested a non-binding E3 control?: Yes
Tested competition with ligand?: No
Tested proteaseome inhibitor?: No
Proteomics data available?: No
Tested engagement in cells?: No
Off-targets reported?: No
Contributed by: Yangwode Jing
E3 ligase: Cereblon
E3 binder: Pomalidomide
SMILES: show
Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O

 Ligand Name: JBJ-07-149 analogue
SMILES: show
O=C(C(C1=CC=CC=C1)N(C2=O)CC3=C2C=C(C=C3)C4=CC=C(C=C4)N5CCNCC5)NC6=NC=CS6

Calculated Values
MW: 941.08
Hbond donors: 3
Hbond acceptors: 14
cLogP: 4.83
TPSA: 192.05

SMILES: show
O=C(C(C1=CC=CC=C1)N(C2=O)CC3=C2C=C(C=C3)C4=CC=C(C=C4)N5CCN(CCOCCOCCOCCNC6=CC=CC7=C6C(N(C7=O)C8CCC(NC8=O)=O)=O)CC5)NC9=NC=CS9

Linker type: PEG
Incubation time (hours): 72
Cells: Ba/F3
EC50 (cells): = 0.161 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
Contributed by: Yangwode Jing
Calculated Values
MW: 969.09
Hbond donors: 3
Hbond acceptors: 14
cLogP: 4.75
TPSA: 209.12

SMILES: show
O=C(C(C1=CC=CC=C1)N(C2=O)CC3=C2C=C(C=C3)C4=CC=C(C=C4)N5CCN(C(CCOCCOCCOCCNC6=CC=CC7=C6C(N(C7=O)C8CCC(NC8=O)=O)=O)=O)CC5)NC9=NC=CS9

Linker type: PEG
Incubation time (hours): 72
Cells: Ba/F3
EC50 (cells): = 0.126 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
Contributed by: Yangwode Jing
Calculated Values
MW: 893.08
Hbond donors: 3
Hbond acceptors: 11
cLogP: 7.12
TPSA: 164.36

SMILES: show
O=C(C(C1=CC=CC=C1)N(C2=O)CC3=C2C=C(C=C3)C4=CC=C(C=C4)N5CCN(CCCCCCCCNC6=CC=CC7=C6C(N(C7=O)C8CCC(NC8=O)=O)=O)CC5)NC9=NC=CS9

Linker type: Alkane
Incubation time (hours): 72
Cells: Ba/F3
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
Contributed by: Yangwode Jing
Calculated Values
MW: 865.03
Hbond donors: 3
Hbond acceptors: 11
cLogP: 6.34
TPSA: 164.36

SMILES: show
O=C(C(C1=CC=CC=C1)N(C2=O)CC3=C2C=C(C=C3)C4=CC=C(C=C4)N5CCN(CCCCCCNC6=CC=CC7=C6C(N(C7=O)C8CCC(NC8=O)=O)=O)CC5)NC9=NC=CS9

Linker type: Alkane
Incubation time (hours): 72
Cells: Ba/F3
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
Contributed by: Yangwode Jing
Calculated Values
MW: 925.04
Hbond donors: 3
Hbond acceptors: 13
cLogP: 4.73
TPSA: 199.89

SMILES: show
O=C(C(C1=CC=CC=C1)N(C2=O)CC3=C2C=C(C=C3)C4=CC=C(C=C4)N5CCN(C(CCOCCOCCNC6=CC=CC7=C6C(N(C7=O)C8CCC(NC8=O)=O)=O)=O)CC5)NC9=NC=CS9

Linker type: PEG
Incubation time (hours): 72
Cells: Ba/F3
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
Contributed by: Yangwode Jing
Calculated Values
MW: 1,056.17
Hbond donors: 4
Hbond acceptors: 16
cLogP: 3.03
TPSA: 247.45

SMILES: show
O=C(C(C1=CC=CC=C1)N(C2=O)CC3=C2C=C(C=C3)C4=CC=C(C=C4)N5CCN(CC(NCCOCCOCCOCCNC(COC6=CC=CC7=C6C(N(C7=O)C8CCC(NC8=O)=O)=O)=O)=O)CC5)NC9=NC=CS9

Linker type: PEG
Incubation time (hours): 72
Cells: Ba/F3
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
Contributed by: Yangwode Jing
Calculated Values
MW: 880.98
Hbond donors: 3
Hbond acceptors: 12
cLogP: 4.71
TPSA: 190.66

SMILES: show
O=C(C(C1=CC=CC=C1)N(C2=O)CC3=C2C=C(C=C3)C4=CC=C(C=C4)N5CCN(C(CCOCCNC6=CC=CC7=C6C(N(C7=O)C8CCC(NC8=O)=O)=O)=O)CC5)NC9=NC=CS9

Linker type: Other
Incubation time (hours): 72
Cells: Ba/F3
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
Contributed by: Yangwode Jing
Calculated Values
MW: 897.03
Hbond donors: 3
Hbond acceptors: 13
cLogP: 4.81
TPSA: 182.82

SMILES: show
O=C(C(C1=CC=CC=C1)N(C2=O)CC3=C2C=C(C=C3)C4=CC=C(C=C4)N5CCN(CCOCCOCCNC6=CC=CC7=C6C(N(C7=O)C8CCC(NC8=O)=O)=O)CC5)NC9=NC=CS9

Linker type: PEG
Incubation time (hours): 72
Cells: Ba/F3
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
Contributed by: Yangwode Jing
Calculated Values
MW: 1,057.20
Hbond donors: 3
Hbond acceptors: 16
cLogP: 4.78
TPSA: 227.58

SMILES: show
O=C(C(C1=CC=CC=C1)N(C2=O)CC3=C2C=C(C=C3)C4=CC=C(C=C4)N5CCN(C(CCOCCOCCOCCOCCOCCNC6=CC=CC7=C6C(N(C7=O)C8CCC(NC8=O)=O)=O)=O)CC5)NC9=NC=CS9

Linker type: PEG
Incubation time (hours): 72
Cells: Ba/F3
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
Contributed by: Yangwode Jing
Calculated Values
MW: 1,013.14
Hbond donors: 3
Hbond acceptors: 15
cLogP: 4.76
TPSA: 218.35

SMILES: show
O=C(C(C1=CC=CC=C1)N(C2=O)CC3=C2C=C(C=C3)C4=CC=C(C=C4)N5CCN(C(CCOCCOCCOCCOCCNC6=CC=CC7=C6C(N(C7=O)C8CCC(NC8=O)=O)=O)=O)CC5)NC9=NC=CS9

Linker type: PEG
Incubation time (hours): 72
Cells: Ba/F3
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
Contributed by: Yangwode Jing
Calculated Values
MW: 952.06
Hbond donors: 4
Hbond acceptors: 13
cLogP: 3.76
TPSA: 219.76

SMILES: show
O=C(C(C1=CC=CC=C1)N(C2=O)CC3=C2C=C(C=C3)C4=CC=C(C=C4)N5CCN(CC(NCCCCNC(COC6=CC=CC7=C6C(N(C7=O)C8CCC(NC8=O)=O)=O)=O)=O)CC5)NC9=NC=CS9

Linker type: Other
Incubation time (hours): 72
Cells: Ba/F3
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
Contributed by: Yangwode Jing
E3 ligase: VHL
E3 binder: Vh032 analogue
SMILES: show
O=C([C@H]1N(C[C@@H](C1)O)C([C@H](C(C)(C)C)N)=O)N[C@@H](C)C2=CC=C(C=C2)C3=C(N=CS3)C

 Ligand Name: JBJ-07-149
IC50: = 1.1 nM
EC50 (cells): = 4.9 μM
SMILES: show
O=C(NC1=NC=CS1)C(N(CC2=C3C=C(C4=CN=C(N5CCNCC5)C=C4)C=C2)C3=O)C6=CC=CC=C6

Calculated Values
MW: 1,141.43
Hbond donors: 4
Hbond acceptors: 16
cLogP: 6.90
TPSA: 220.99

SMILES: show
O=C(C(C1=CC=CC=C1)N(C2=O)CC3=C2C=C(C=C3)C4=CN=C(C=C4)N5CCN(CCOCCOCCOCCC(N[C@@H](C(C)(C)C)C(N(C[C@@H](C6)O)[C@@H]6C(N[C@@H](C)C7=CC=C(C=C7)C8=C(N=CS8)C)=O)=O)=O)CC5)NC9=NC=CS9

Linker type: PEG
Incubation time (hours): 72
Cells: Ba/F3
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
Contributed by: Yangwode Jing
Calculated Values
MW: 1,097.38
Hbond donors: 4
Hbond acceptors: 15
cLogP: 6.89
TPSA: 211.76

SMILES: show
O=C(C(C1=CC=CC=C1)N(C2=O)CC3=C2C=C(C=C3)C4=CN=C(C=C4)N5CCN(CCOCCOCCC(N[C@@H](C(C)(C)C)C(N(C[C@@H](C6)O)[C@@H]6C(N[C@@H](C)C7=CC=C(C=C7)C8=C(N=CS8)C)=O)=O)=O)CC5)NC9=NC=CS9

Linker type: PEG
Incubation time (hours): 72
Cells: Ba/F3
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
Contributed by: Yangwode Jing