Target Binding Site Detail

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Target General Information
Ligand General Information
Drug Binding Sites of Target
References
Target General Information  Top
Target ID T40474 Target Info
Target Name Proto-oncogene c-Met (MET)
Synonyms Tyrosine-protein kinase Met; Scatter factor receptor; SF receptor; Met proto-oncogene tyrosine kinase; Hepatocyte growth factor receptor; HGF/SF receptor; HGF-SF receptor; HGF receptor; C-met; C-Met receptor tyrosine kinase
Target Type Successful Target
Gene Name MET
Biochemical Class Kinase
UniProt ID
MET_HUMAN
Ligand General Information  Top
Ligand Name BMS-777607 Ligand Info
Canonical SMILES CCOC1=C(C(=O)N(C=C1)C2=CC=C(C=C2)F)C(=O)NC3=CC(=C(C=C3)OC4=C(C(=NC=C4)N)Cl)F
InChI 1S/C25H19ClF2N4O4/c1-2-35-19-10-12-32(16-6-3-14(27)4-7-16)25(34)21(19)24(33)31-15-5-8-18(17(28)13-15)36-20-9-11-30-23(29)22(20)26/h3-13H,2H2,1H3,(H2,29,30)(H,31,33)
InChIKey VNBRGSXVFBYQNN-UHFFFAOYSA-N
PubChem Compound ID 24794418
Drug Binding Sites of Target  Top
PDB ID: 3F82      Crystal structure of the tyrosine kinase domain of the hepatocyte growth factor receptor C-MET in complex with N-(4-(2-amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide
Method X-ray diffraction Resolution 2.50 Å Mutation Yes [1]
PDB Sequence
LSALNPELVQ
1064
AVQHVVIGPS
1074
SLIVHFNEVI
1084
GRGHFGCVYH
1094
GTLLKIHCAV
1109

KSLNRGEVSQ
1123
FLTEGIIMKD
1133
FSHPNVLSLL
1143
GICLRSEGSP
1153
LVVLPYMKHG
1163

DLRNFIRNET
1173
HNPTVKDLIG
1183
FGLQVAKGMK
1193
FLASKKFVHR
1203
DLAARNCMLD
1213

EKFTVKVADF
1223
GKLPVKWMAL
1252
ESLQTQKFTT
1262
KSDVWSFGVL
1272
LWELMTRGAP
1282

PYPDVNTFDI
1292
TVYLLQGRRL
1302
LQPEYCPDPL
1312
YEVMLKCWHP
1322
KAEMRPSFSE
1332

LVSRISAIFS
1342
TFIGEHYVHV
1352
NATYVNVK
Residue
Distance (Å)
ILE1084
2.974
VAL1092
3.188
ALA1108
3.367
VAL1109
4.914
LYS1110
2.806
PHE1124
3.568
GLU1127
3.535
GLY1128
4.078
MET1131
3.560
PHE1134
3.674
VAL1139
3.787
LEU1140
3.853
VAL1155
3.721
Residue
Distance (Å)
LEU1157
3.325
PRO1158
3.150
TYR1159
3.552
MET1160
2.855
GLY1163
4.289
LEU1195
3.054
PHE1200
3.742
HIS1202
3.733
MET1211
3.479
VAL1220
3.447
ALA1221
3.463
ASP1222
2.880
PHE1223
3.333
PDB ID: 6SDD      Crystal structure of D1228V cMET bound by BMS-777607
Method X-ray diffraction Resolution 1.93 Å Mutation Yes [2]
PDB Sequence
LVQAVQHVVI
1071
GPSSLIVHFN
1081
EVIGHFGCVY
1093
HGTLLDNDGK
1103
KIHCAVKSLN
1113

VSQFLTEGII
1130
MKDFSHPNVL
1140
SLLGICLRSP
1153
LVVLPYMKHG
1163
DLRNFIRNET
1173

HNPTVKDLIG
1183
FGLQVAKGMK
1193
YLASKKFVHR
1203
DLAARNCMLD
1213
EKFTVKVADF
1223

GLARVMYDKE
1233
YYSVHNKTGA
1243
KLPVKWMALE
1253
SLQTQKFTTK
1263
SDVWSFGVLL
1273

WELMTRGAPP
1283
YPDVNTFDIT
1293
VYLLQGRRLL
1303
QPEYCPDPLY
1313
EVMLKCWHPK
1323

AEMRPSFSEL
1333
VSRISAIFST
1343
F
Residue
Distance (Å)
ILE1084
3.623
VAL1092
3.727
ALA1108
3.484
LYS1110
3.044
PHE1124
4.166
GLU1127
4.140
GLY1128
4.540
MET1131
3.488
PHE1134
3.884
VAL1139
3.983
LEU1140
3.642
LEU1142
4.768
ILE1145
4.285
VAL1155
3.828
Residue
Distance (Å)
LEU1157
3.512
PRO1158
3.468
TYR1159
3.803
MET1160
3.097
GLY1163
4.519
LEU1195
3.247
PHE1200
3.742
HIS1202
3.758
MET1211
3.503
VAL1220
3.436
ALA1221
3.483
ASP1222
2.876
PHE1223
3.313
References  Top
REF 1 Discovery of N-(4-(2-amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (BMS-777607... J Med Chem. 2009 Mar 12;52(5):1251-4.
REF 2 Structural and Molecular Insight into Resistance Mechanisms of First Generation cMET Inhibitors. ACS Med Chem Lett. 2019 Aug 2;10(9):1322-1327.

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