PROTACpedia
Design and synthesis of selective degraders of EGFR(L858R/T790M) mutant. Eur J Med Chem. 2020 Apr 15;192:112199. PMID:32171162 DOI:10.1016/j.ejmech.2020.112199
Target: EGFR Epidermal growth factor receptor P00533 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: XTF-262
Ligand PDB Id: F62
PDB with Ligand: 5GMP
IC50: < 4 nM
SMILES: show
C=CC(=O)Nc1cccc(-n2c(=O)cc(C)c3cnc(Nc4ccc(N5CCN(C)CC5)cc4OC)nc32)c1

Calculated Values
MW: 1,038.29
Hbond donors: 5
Hbond acceptors: 15
cLogP: 6.89
TPSA: 216.25

SMILES: show
C=CC(=O)Nc1cccc(-n2c(=O)cc(C)c3cnc(Nc4ccc(N5CCN(CCCCCC(=O)N[C@H](C(=O)N6C[C@H](O)C[C@H]6C(=O)NCc6ccc(-c7scnc7C)cc6)C(C)(C)C)CC5)cc4OC)nc32)c1

Linker type: Alkane
Incubation time (hours): 16
Cells: H1975
DC50: = 5.9 nM
Dmax: = 100 %
Tested a non-binding E3 control?: No
Tested competition with ligand?: Yes
Tested proteaseome inhibitor?: Yes
Proteomics data available?: No
Tested engagement in cells?: No
Off-targets reported?: No
Comments: Ligand IC50 is 0.26 nM (Kd), 4.0 nM (kinase activity). EC50 of PROTAC was measured in H1975 cell line
Contributed by: Ronen Gabizon
Calculated Values
MW: 1,136.43
Hbond donors: 5
Hbond acceptors: 15
cLogP: 8.76
TPSA: 233.32

SMILES: show
C=CC(=O)Nc1cccc(-n2c(=O)cc(C)c3cnc(Nc4ccc(N5CCN(C(=O)CCCCCCCCCCC(=O)N[C@H](C(=O)N6C[C@H](O)C[C@H]6C(=O)NCc6ccc(-c7scnc7C)cc6)C(C)(C)C)CC5)cc4OC)nc32)c1

Linker type: Alkane
Incubation time (hours): 16
Cells: H1975
DC50: = 313 nM
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: Ligand IC50 is 0.26 nM (Kd), 4.0 nM (kinase activity)
Contributed by: Ronen Gabizon
Calculated Values
MW: 1,080.33
Hbond donors: 5
Hbond acceptors: 15
cLogP: 7.20
TPSA: 233.32

SMILES: show
C=CC(=O)Nc1cccc(-n2c(=O)cc(C)c3cnc(Nc4ccc(N5CCN(C(=O)CCCCCCC(=O)N[C@H](C(=O)N6C[C@H](O)C[C@H]6C(=O)NCc6ccc(-c7scnc7C)cc6)C(C)(C)C)CC5)cc4OC)nc32)c1

Linker type: Alkane
Incubation time (hours): 16
Cells: H1975
DC50: = 235 nM
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: Ligand IC50 is 0.26 nM (Kd), 4.0 nM (kinase activity)
Contributed by: Ronen Gabizon
Calculated Values
MW: 1,094.40
Hbond donors: 5
Hbond acceptors: 15
cLogP: 8.45
TPSA: 216.25

SMILES: show
C=CC(=O)Nc1cccc(-n2c(=O)cc(C)c3cnc(Nc4ccc(N5CCN(CCCCCCCCCC(=O)N[C@H](C(=O)N6C[C@H](O)C[C@H]6C(=O)NCc6ccc(-c7scnc7C)cc6)C(C)(C)C)CC5)cc4OC)nc32)c1

Linker type: Alkane
Incubation time (hours): 16
Cells: H1975
DC50: = 132 nM
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: Ligand IC50 is 0.26 nM (Kd), 4.0 nM (kinase activity)
Contributed by: Ronen Gabizon
Calculated Values
MW: 1,066.34
Hbond donors: 5
Hbond acceptors: 15
cLogP: 7.67
TPSA: 216.25

SMILES: show
C=CC(=O)Nc1cccc(-n2c(=O)cc(C)c3cnc(Nc4ccc(N5CCN(CCCCCCCC(=O)N[C@H](C(=O)N6C[C@H](O)C[C@H]6C(=O)NCc6ccc(-c7scnc7C)cc6)C(C)(C)C)CC5)cc4OC)nc32)c1

Linker type: Alkane
Incubation time (hours): 16
Cells: H1975
DC50: = 466 nM
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: Ligand IC50 is 0.26 nM (Kd), 4.0 nM (kinase activity)
Contributed by: Ronen Gabizon
Calculated Values
MW: 1,108.38
Hbond donors: 5
Hbond acceptors: 15
cLogP: 7.98
TPSA: 233.32

SMILES: show
C=CC(=O)Nc1cccc(-n2c(=O)cc(C)c3cnc(Nc4ccc(N5CCN(C(=O)CCCCCCCCC(=O)N[C@H](C(=O)N6C[C@H](O)C[C@H]6C(=O)NCc6ccc(-c7scnc7C)cc6)C(C)(C)C)CC5)cc4OC)nc32)c1

Linker type: Alkane
Incubation time (hours): 16
Cells: H1975
DC50: = 69 nM
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: Ligand IC50 is 0.26 nM (Kd), 4.0 nM (kinase activity)
Contributed by: Ronen Gabizon
Calculated Values
MW: 1,122.45
Hbond donors: 5
Hbond acceptors: 15
cLogP: 9.23
TPSA: 216.25

SMILES: show
C=CC(=O)Nc1cccc(-n2c(=O)cc(C)c3cnc(Nc4ccc(N5CCN(CCCCCCCCCCCC(=O)N[C@H](C(=O)N6C[C@H](O)C[C@H]6C(=O)NCc6ccc(-c7scnc7C)cc6)C(C)(C)C)CC5)cc4OC)nc32)c1

Linker type: Alkane
Incubation time (hours): 16
Cells: H1975
DC50: = 25.3 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?: WT EGFR, 50 nM
Comments: Ligand IC50 is 0.26 nM (Kd), 4.0 nM (kinase activity)
Contributed by: Ronen Gabizon
Calculated Values
MW: 1,052.27
Hbond donors: 5
Hbond acceptors: 15
cLogP: 6.42
TPSA: 233.32

SMILES: show
C=CC(=O)Nc1cccc(-n2c(=O)cc(C)c3cnc(Nc4ccc(N5CCN(C(=O)CCCCC(=O)N[C@H](C(=O)N6C[C@H](O)C[C@H]6C(=O)NCc6ccc(-c7scnc7C)cc6)C(C)(C)C)CC5)cc4OC)nc32)c1

Linker type: Alkane
Incubation time (hours): 16
Cells: H1975
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: Ligand IC50 is 0.26 nM (Kd), 4.0 nM (kinase activity)
Contributed by: Ronen Gabizon
Calculated Values
MW: 1,010.23
Hbond donors: 5
Hbond acceptors: 15
cLogP: 6.11
TPSA: 216.25

SMILES: show
C=CC(=O)Nc1cccc(-n2c(=O)cc(C)c3cnc(Nc4ccc(N5CCN(CCCC(=O)N[C@H](C(=O)N6C[C@H](O)C[C@H]6C(=O)NCc6ccc(-c7scnc7C)cc6)C(C)(C)C)CC5)cc4OC)nc32)c1

Linker type: Alkane
Incubation time (hours): 16
Cells: H1975
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: Ligand IC50 is 0.26 nM (Kd), 4.0 nM (kinase activity)
Contributed by: Ronen Gabizon
E3 ligase: Mdm2
E3 binder: Mdm2 Binder
SMILES: show
COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F

 Ligand Name: XTF-262
Ligand PDB Id: F62
PDB with Ligand: 5GMP
IC50: < 4 nM
SMILES: show
C=CC(=O)Nc1cccc(-n2c(=O)cc(C)c3cnc(Nc4ccc(N5CCN(C)CC5)cc4OC)nc32)c1

Calculated Values
MW: 1,307.38
Hbond donors: 5
Hbond acceptors: 14
cLogP: 13.50
TPSA: 224.94

SMILES: show
C=CC(=O)Nc1cccc(-n2c(=O)cc(C)c3cnc(Nc4ccc(N5CCN(C(=O)CCCCCCCCCCCNC(=O)c6ccc(NC(=O)[C@@H]7N[C@@H](CC(C)(C)C)[C@](C#N)(c8ccc(Cl)cc8F)[C@H]7c7cccc(Cl)c7F)c(OC)c6)CC5)cc4OC)nc32)c1

Linker type: Alkane
Incubation time (hours): 16
Cells: H1975
DC50: = 264 nM
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: Ligand IC50 is 0.26 nM (Kd), 4.0 nM (kinase activity)
Contributed by: Ronen Gabizon
Calculated Values
MW: 1,279.33
Hbond donors: 5
Hbond acceptors: 14
cLogP: 12.72
TPSA: 224.94

SMILES: show
C=CC(=O)Nc1cccc(-n2c(=O)cc(C)c3cnc(Nc4ccc(N5CCN(C(=O)CCCCCCCCCNC(=O)c6ccc(NC(=O)[C@@H]7N[C@@H](CC(C)(C)C)[C@](C#N)(c8ccc(Cl)cc8F)[C@H]7c7cccc(Cl)c7F)c(OC)c6)CC5)cc4OC)nc32)c1

Linker type: Alkane
Incubation time (hours): 16
Cells: H1975
DC50: = 77 nM
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: Ligand IC50 is 0.26 nM (Kd), 4.0 nM (kinase activity)
Contributed by: Ronen Gabizon
Calculated Values
MW: 1,293.40
Hbond donors: 5
Hbond acceptors: 14
cLogP: 13.97
TPSA: 207.87

SMILES: show
C=CC(=O)Nc1cccc(-n2c(=O)cc(C)c3cnc(Nc4ccc(N5CCN(CCCCCCCCCCCCNC(=O)c6ccc(NC(=O)[C@@H]7N[C@@H](CC(C)(C)C)[C@](C#N)(c8ccc(Cl)cc8F)[C@H]7c7cccc(Cl)c7F)c(OC)c6)CC5)cc4OC)nc32)c1

Linker type: Alkane
Incubation time (hours): 16
Cells: H1975
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: Ligand IC50 is 0.26 nM (Kd), 4.0 nM (kinase activity)
Contributed by: Ronen Gabizon
Calculated Values
MW: 1,251.28
Hbond donors: 5
Hbond acceptors: 14
cLogP: 11.94
TPSA: 224.94

SMILES: show
C=CC(=O)Nc1cccc(-n2c(=O)cc(C)c3cnc(Nc4ccc(N5CCN(C(=O)CCCCCCCNC(=O)c6ccc(NC(=O)[C@@H]7N[C@@H](CC(C)(C)C)[C@](C#N)(c8ccc(Cl)cc8F)[C@H]7c7cccc(Cl)c7F)c(OC)c6)CC5)cc4OC)nc32)c1

Linker type: Alkane
Incubation time (hours): 16
Cells: H1975
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: Ligand IC50 is 0.26 nM (Kd), 4.0 nM (kinase activity)
Contributed by: Ronen Gabizon
Calculated Values
MW: 1,223.22
Hbond donors: 5
Hbond acceptors: 14
cLogP: 11.16
TPSA: 224.94

SMILES: show
C=CC(=O)Nc1cccc(-n2c(=O)cc(C)c3cnc(Nc4ccc(N5CCN(C(=O)CCCCCNC(=O)c6ccc(NC(=O)[C@@H]7N[C@@H](CC(C)(C)C)[C@](C#N)(c8ccc(Cl)cc8F)[C@H]7c7cccc(Cl)c7F)c(OC)c6)CC5)cc4OC)nc32)c1

Linker type: Alkane
Incubation time (hours): 16
Cells: H1975
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: Ligand IC50 is 0.26 nM (Kd), 4.0 nM (kinase activity)
Contributed by: Ronen Gabizon
E3 ligase: Iap
E3 binder: Bestatin
SMILES: show
CC(C)C[C@H](NC(=O)[C@@H](O)[C@H](N)Cc1ccccc1)C(=O)O

 Ligand Name: XTF-262
Ligand PDB Id: F62
PDB with Ligand: 5GMP
IC50: < 4 nM
SMILES: show
C=CC(=O)Nc1cccc(-n2c(=O)cc(C)c3cnc(Nc4ccc(N5CCN(C)CC5)cc4OC)nc32)c1

Calculated Values
MW: 999.27
Hbond donors: 6
Hbond acceptors: 13
cLogP: 7.09
TPSA: 226.14

SMILES: show
C=CC(=O)Nc1cccc(-n2c(=O)cc(C)c3cnc(Nc4ccc(N5CCN(C(=O)CCCCCCCCCCCNC(=O)[C@H](CC(C)C)NC(=O)[C@@H](O)[C@H](N)Cc6ccccc6)CC5)cc4OC)nc32)c1

Linker type: Alkane
Incubation time (hours): 16
Cells: H1975
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: Ligand IC50 is 0.26 nM (Kd), 4.0 nM (kinase activity)
Contributed by: Ronen Gabizon
E3 ligase: Cereblon
E3 binder: Pomalidomide
SMILES: show
Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O

 Ligand Name: XTF-262
Ligand PDB Id: F62
PDB with Ligand: 5GMP
IC50: < 4 nM
SMILES: show
C=CC(=O)Nc1cccc(-n2c(=O)cc(C)c3cnc(Nc4ccc(N5CCN(C)CC5)cc4OC)nc32)c1

Calculated Values
MW: 979.11
Hbond donors: 4
Hbond acceptors: 14
cLogP: 6.56
TPSA: 234.34

SMILES: show
C=CC(=O)Nc1cccc(-n2c(=O)cc(C)c3cnc(Nc4ccc(N5CCN(C(=O)CCCCCCCCCCC(=O)Nc6cccc7c6C(=O)N(C6CCC(=O)NC6=O)C7=O)CC5)cc4OC)nc32)c1

Linker type: Alkane
Incubation time (hours): 16
Cells: H1975
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: Ligand IC50 is 0.26 nM (Kd), 4.0 nM (kinase activity)
Contributed by: Ronen Gabizon