PROTACpedia
The Advantages of Targeted Protein Degradation Over Inhibition: An RTK Case Study. Cell Chem Biol. 2018 Jan 18;25(1):67-77.e3. PMID:29129716 DOI:10.1016/j.chembiol.2017.09.009
Target: MET Hepatocyte growth factor receptor P08581 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: foretinib-based
Ligand PDB Id: 88Z
PDB with Ligand: 6SD9
SMILES: show
COc1cc2c(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3F)ccnc2cc1OCCCN1CCOCC1

Calculated Values
MW: 1,106.26
Hbond donors: 4
Hbond acceptors: 14
cLogP: 8.07
TPSA: 234.07

SMILES: show
COc1cc2c(Oc3ccc(N(C(=O)C4(C(N)=O)CC4)c4ccc(F)cc4)cc3F)ccnc2cc1OCCCOCCCOCCC(=O)N[C@H](C(=O)N1C[C@H](O)C[C@H]1C(=O)NCc1ccc(-c2scnc2C)cc1)C(C)(C)C

Linker type: non-PEG polyether
Incubation time (hours): 24
Cells: MDA-MB-231, GTL16
Tested a non-binding E3 control?: Yes
Tested competition with ligand?: No
Tested proteaseome inhibitor?: Yes
Proteomics data available?: No
Tested engagement in cells?: Yes
Off-targets reported?: No
Contributed by: Barr Tivon
Target: ERBB2 Receptor tyrosine-protein kinase erbB-2 P04626 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: lapatinib-based
Ligand PDB Id: FMM
PDB with Ligand: 1XKK
SMILES: show
CS(=O)(=O)CCNCc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c3c2)o1

Calculated Values
MW: 1,030.62
Hbond donors: 4
Hbond acceptors: 13
cLogP: 9.06
TPSA: 186.36

SMILES: show
Cc1ncsc1-c1ccc(CNC(=O)[C@@H]2C[C@@H](O)CN2C(=O)[C@@H](NC(=O)COCCOCCOc2ccc(-c3ccc4ncnc(Nc5ccc(OCc6cccc(F)c6)c(Cl)c5)c4c3)cc2)C(C)(C)C)cc1

Linker type: PEG
Incubation time (hours): 24
Cells: OVCAR8 (WT EGFR), HeLa (EGFR Exon 20 Ins), SKBr3 (HER2)
DC50: = 39.2 nM
Dmax: = 97.6 %
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: DC50 is for WT EGFR. DC50 for EGFR Exon 20 Ins is 736.2 nM. DMAX is for WT EGFR. DMAX for EGFR Exon 20 Ins is 68.8 %.
Contributed by: Barr Tivon
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: gefitinib-based
Ligand PDB Id: IRE
PDB with Ligand: 4WKQ
SMILES: show
COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCCCN1CCOCC1

Calculated Values
MW: 934.53
Hbond donors: 4
Hbond acceptors: 13
cLogP: 7.39
TPSA: 186.36

SMILES: show
COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCCCCCOCCOCCC(=O)N[C@H](C(=O)N1C[C@H](O)C[C@H]1C(=O)NCc1ccc(-c2scnc2C)cc1)C(C)(C)C

Linker type: PEG
Incubation time (hours): 24
Cells: HCC827 (Exon 19 del), H3255 (L858R)
DC50: = 11.7 nM
Dmax: = 98.9 %
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: DC50 is for EGFR (Exon 19 del). DC50 for EGFR (L858R) 22.3 nM. DMAX is for EGFR (Exon 19 del). DMAX for EGFR (L858R) 96.6 %.
Contributed by: Barr Tivon
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: lapatinib-based
Ligand PDB Id: FMM
PDB with Ligand: 1XKK
SMILES: show
CS(=O)(=O)CCNCc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c3c2)o1

Calculated Values
MW: 1,030.62
Hbond donors: 4
Hbond acceptors: 13
cLogP: 9.06
TPSA: 186.36

SMILES: show
Cc1ncsc1-c1ccc(CNC(=O)[C@@H]2C[C@@H](O)CN2C(=O)[C@@H](NC(=O)COCCOCCOc2ccc(-c3ccc4ncnc(Nc5ccc(OCc6cccc(F)c6)c(Cl)c5)c4c3)cc2)C(C)(C)C)cc1

Linker type: PEG
Incubation time (hours): 24
Cells: OVCAR8 (WT EGFR), HeLa (EGFR Exon 20 Ins), SKBr3 (HER2)
DC50: = 39.2 nM
Dmax: = 97.6 %
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: DC50 is for WT EGFR. DC50 for EGFR Exon 20 Ins is 736.2 nM. DMAX is for WT EGFR. DMAX for EGFR Exon 20 Ins is 68.8 %.
Contributed by: Barr Tivon
Calculated Values
MW: 1,074.67
Hbond donors: 4
Hbond acceptors: 14
cLogP: 9.08
TPSA: 195.59

SMILES: show
Cc1ncsc1-c1ccc(CNC(=O)[C@@H]2C[C@@H](O)CN2C(=O)[C@@H](NC(=O)COCCOCCOCCOc2ccc(-c3ccc4ncnc(Nc5ccc(OCc6cccc(F)c6)c(Cl)c5)c4c3)cc2)C(C)(C)C)cc1

Linker type: PEG
Incubation time (hours): 24
Cells: OVCAR8
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: Barr Tivon
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: afatinib-based
Ligand PDB Id: 0WN
PDB with Ligand: 4G5J
SMILES: show
CN(C)C/C=C/C(=O)Nc1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1OC1CCOC1

Calculated Values
MW: 1,086.77
Hbond donors: 5
Hbond acceptors: 14
cLogP: 9.00
TPSA: 209.47

SMILES: show
Cc1ncsc1-c1ccc(CNC(=O)[C@@H]2C[C@@H](O)CN2C(=O)[C@@H](NC(=O)CCCCCOCCCCOCCCCOc2cc3ncnc(Nc4ccc(F)c(Cl)c4)c3cc2NC(=O)/C=C/CN(C)C)C(C)(C)C)cc1

Linker type: non-PEG polyether
Incubation time (hours): 24
Cells: H1975
DC50: = 215.8 nM
Dmax: = 79.1 %
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: Barr Tivon