Target Binding Site Detail
| Target General Information | Top | ||||
|---|---|---|---|---|---|
| Target ID | T56418 | Target Info | |||
| Target Name | ALK tyrosine kinase receptor (ALK) | ||||
| Synonyms | CD246; Anaplastic lymphoma kinase | ||||
| Target Type | Successful Target | ||||
| Gene Name | ALK | ||||
| Biochemical Class | Kinase | ||||
| UniProt ID | |||||
| Ligand General Information | Top | ||||
|---|---|---|---|---|---|
| Ligand Name | PF-06463922 | Ligand Info | |||
| Canonical SMILES | CC1C2=C(C=CC(=C2)F)C(=O)N(CC3=NN(C(=C3C4=CC(=C(N=C4)N)O1)C#N)C)C | ||||
| InChI | 1S/C21H19FN6O2/c1-11-15-7-13(22)4-5-14(15)21(29)27(2)10-16-19(17(8-23)28(3)26-16)12-6-18(30-11)20(24)25-9-12/h4-7,9,11H,10H2,1-3H3,(H2,24,25)/t11-/m1/s1 | ||||
| InChIKey | IIXWYSCJSQVBQM-LLVKDONJSA-N | ||||
| PubChem Compound ID | 71731823 | ||||
| Drug Binding Sites of Target | Top | |||||
|---|---|---|---|---|---|---|
| PDB ID: 5A9U Structure of C1156Y Mutant Human Anaplastic Lymphoma Kinase in Complex with PF-06463922 ((10R)-7-amino-12-fluoro-2,10,16-trimethyl- 15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo(4,3-h)(2,5,11) benzoxadiazacyclotetradecine-3-carbonitrile). | ||||||
| Method | X-ray diffraction | Resolution | 1.60 Å | Mutation | Yes | [1] |
| PDB Sequence |
NPNYCFAGKT
1102 SSISDLKEVP1112 RKNITLIRGL1122 GHGEVYEGQV1135 PLQVAVKTLP1153 EVYSEQDELD 1163 FLMEALIISK1173 FNHQNIVRCI1183 GVSLQSLPRF1193 ILLELMAGGD1203 LKSFLRETRP 1213 RPSQPSSLAM1223 LDLLHVARDI1233 ACGCQYLEEN1243 HFIHRDIAAR1253 NCLLTCPGPG 1263 RVAKIGDFGM1273 ARDIYRGGCA1289 MLPVKWMPPE1299 AFMEGIFTSK1309 TDTWSFGVLL 1319 WEIFSLGYMP1329 YPSKSNQEVL1339 EFVTSGGRMD1349 PPKNCPGPVY1359 RIMTQCWQHQ 1369 PEDRPNFAII1379 LERIEYCTQD1389 PDVINTALPI1399 EYG
|
|||||
|
|
LEU1122
3.454
GLY1123
3.270
HIS1124
4.786
VAL1130
3.450
ALA1148
3.425
LYS1150
4.134
VAL1180
4.080
LEU1196
3.639
GLU1197
2.884
LEU1198
3.732
|
|||||
| PDB ID: 4CLJ Structure of L1196M Mutant Human Anaplastic Lymphoma Kinase in Complex with PF-06463922 ((10R)-7-amino-12-fluoro-2,10,16-trimethyl- 15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo(4,3-h)(2,5,11) benzoxadiazacyclotetradecine-3-carbonitrile). | ||||||
| Method | X-ray diffraction | Resolution | 1.66 Å | Mutation | Yes | [2] |
| PDB Sequence |
PNYCFAGKTS
1103 SISDLKEVPR1113 KNITLIRGLG1123 HGAFGEVYEG1133 QVSPLQVAVK1150 TLPEVCSEQD 1160 ELDFLMEALI1170 ISKFNHQNIV1180 RCIGVSLQSL1190 PRFILMELMA1200 GGDLKSFLRE 1210 TRPRPSQPSS1220 LAMLDLLHVA1230 RDIACGCQYL1240 EENHFIHRDI1250 AARNCLLTCP 1260 GPGRVAKIGD1270 FGMARDIYRG1286 GCAMLPVKWM1296 PPEAFMEGIF1306 TSKTDTWSFG 1316 VLLWEIFSLG1326 YMPYPSKSNQ1336 EVLEFVTSGG1346 RMDPPKNCPG1356 PVYRIMTQCW 1366 QHQPEDRPNF1376 AIILERIEYC1386 TQDPDVINTA1396 LPIEYG
|
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|
|
LEU1122
3.148
GLY1123
3.253
VAL1130
3.460
ALA1148
3.444
LYS1150
4.228
VAL1180
4.070
MET1196
3.639
GLU1197
2.904
LEU1198
3.626
MET1199
2.892
|
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| PDB ID: 5AA8 Structure of C1156Y,L1198F Mutant Human Anaplastic Lymphoma Kinase in Complex with PF-06463922 ((10R)-7-amino-12-fluoro-2,10,16-trimethyl- 15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo(4,3-h)(2,5,11) benzoxadiazacyclotetradecine-3-carbonitrile). | ||||||
| Method | X-ray diffraction | Resolution | 1.86 Å | Mutation | Yes | [1] |
| PDB Sequence |
NPNYCFAGKT
1102 SSISDLKEVP1112 RKNITLIRGL1122 GHGEVYEGQV1135 PLQVAVKTLP1153 EVYSEQDELD 1163 FLMEALIISK1173 FNHQNIVRCI1183 GVSLQSLPRF1193 ILLEFMAGGD1203 LKSFLRETRP 1213 RPSQPSSLAM1223 LDLLHVARDI1233 ACGCQYLEEN1243 HFIHRDIAAR1253 NCLLTCPGPG 1263 RVAKIGDFGM1273 ARDIYRGGCA1289 MLPVKWMPPE1299 AFMEGIFTSK1309 TDTWSFGVLL 1319 WEIFSLGYMP1329 YPSKSNQEVL1339 EFVTSGGRMD1349 PPKNCPGPVY1359 RIMTQCWQHQ 1369 PEDRPNFAII1379 LERIEYCTQD1389 PDVINTALPI1399 EYG
|
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|
|
LEU1122
3.424
GLY1123
3.427
HIS1124
4.433
VAL1130
3.413
ALA1148
3.321
LYS1150
4.042
VAL1180
4.258
LEU1196
3.749
GLU1197
2.812
PHE1198
3.289
|
|||||
| PDB ID: 5AA9 Structure of L1198F Mutant Human Anaplastic Lymphoma Kinase in Complex with PF-06463922 ((10R)-7-amino-12-fluoro-2,10,16-trimethyl- 15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo(4,3-h)(2,5,11) benzoxadiazacyclotetradecine-3-carbonitrile). | ||||||
| Method | X-ray diffraction | Resolution | 1.93 Å | Mutation | Yes | [1] |
| PDB Sequence |
NPNYCFAGKT
1102 SSISDLKEVP1112 RKNITLIRGL1122 GHGAFGEVYE1132 GQVPLQVAVK1150 TLPEVCSEQD 1160 ELDFLMEALI1170 ISKFNHQNIV1180 RCIGVSLQSL1190 PRFILLEFMA1200 GGDLKSFLRE 1210 TRPRPSQPSS1220 LAMLDLLHVA1230 RDIACGCQYL1240 EENHFIHRDI1250 AARNCLLTCP 1260 GPGRVAKIGD1270 FGMARDIYRG1286 GCAMLPVKWM1296 PPEAFMEGIF1306 TSKTDTWSFG 1316 VLLWEIFSLG1326 YMPYPSKSNQ1336 EVLEFVTSGG1346 RMDPPKNCPG1356 PVYRIMTQCW 1366 QHQPEDRPNF1376 AIILERIEYC1386 TQDPDVINTA1396 LPIEYG
|
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Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .5P8 or .5P82 or .5P83 or :35P8;style chemicals stick;color identity;select .A:1122 or .A:1123 or .A:1130 or .A:1148 or .A:1150 or .A:1196 or .A:1197 or .A:1198 or .A:1199 or .A:1200 or .A:1202 or .A:1203 or .A:1253 or .A:1254 or .A:1255 or .A:1256 or .A:1269 or .A:1270; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
|
||||||
| PDB ID: 4CLI Structure of the Human Anaplastic Lymphoma Kinase in Complex with PF- 06463922 ((10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16, 17-tetrahydro-2H-8,4-(metheno)pyrazolo(4,3-h)(2,5,11) benzoxadiazacyclotetradecine-3-carbonitrile). | ||||||
| Method | X-ray diffraction | Resolution | 2.05 Å | Mutation | No | [2] |
| PDB Sequence |
NPNYCFAGKT
1102 SSISDLKEVP1112 RKNITLIRGL1122 GHGAFGEVYE1132 GQVPLQVAVK1150 TLPEVCSEQD 1160 ELDFLMEALI1170 ISKFNHQNIV1180 RCIGVSLQSL1190 PRFILLELMA1200 GGDLKSFLRE 1210 TRPRPSQPSS1220 LAMLDLLHVA1230 RDIACGCQYL1240 EENHFIHRDI1250 AARNCLLTCP 1260 GPGRVAKIGD1270 FGMARDIYRG1286 GCAMLPVKWM1296 PPEAFMEGIF1306 TSKTDTWSFG 1316 VLLWEIFSLG1326 YMPYPSKSNQ1336 EVLEFVTSGG1346 RMDPPKNCPG1356 PVYRIMTQCW 1366 QHQPEDRPNF1376 AIILERIEYC1386 TQDPDVINTA1396 LPIEY
|
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|
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .5P8 or .5P82 or .5P83 or :35P8;style chemicals stick;color identity;select .A:1122 or .A:1123 or .A:1130 or .A:1148 or .A:1150 or .A:1180 or .A:1196 or .A:1197 or .A:1198 or .A:1199 or .A:1200 or .A:1202 or .A:1203 or .A:1253 or .A:1254 or .A:1255 or .A:1256 or .A:1269 or .A:1270; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
|
LEU1122
3.379
GLY1123
4.022
VAL1130
3.398
ALA1148
3.348
LYS1150
4.049
VAL1180
3.975
LEU1196
3.505
GLU1197
2.812
LEU1198
3.678
MET1199
2.829
|
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| References | Top | ||||
|---|---|---|---|---|---|
| REF 1 | Resensitization to Crizotinib by the Lorlatinib ALK Resistance Mutation L1198F. N Engl J Med. 2016 Jan 7;374(1):54-61. | ||||
| REF 2 | Discovery of (10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]-benzoxadiazacyclotetradecine-3-carbonitrile (PF-06463922), a macrocyclic inhibitor of anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) with preclinical brain exposure and broad-spectrum potency against ALK-resistant mutations. J Med Chem. 2014 Jun 12;57(11):4720-44. | ||||
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