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 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
ALK_HUMAN
Ligand General Information  Top
Ligand Name (2R)-2-[5-(6-amino-5-{(1R)-1-[2-(1,3-dihydro-2H-1,2,3-triazol-2-yl)-5-fluorophenyl]ethoxy}pyridin-3-yl)-4-methyl-1,3-thiazol-2-yl]propane-1,2-diol Ligand Info
Canonical SMILES CC1=C(SC(=N1)C(C)(CO)O)C2=CC(=C(N=C2)N)OC(C)C3=C(C=CC(=C3)F)N4NC=CN4
InChI 1S/C22H25FN6O3S/c1-12-19(33-21(28-12)22(3,31)11-30)14-8-18(20(24)25-10-14)32-13(2)16-9-15(23)4-5-17(16)29-26-6-7-27-29/h4-10,13,26-27,30-31H,11H2,1-3H3,(H2,24,25)/t13-,22-/m1/s1
InChIKey MXETZPYUZKZIMB-MCMMXHMISA-N
PubChem Compound ID 137348958
Drug Binding Sites of Target  Top
PDB ID: 4CD0      Structure of L1196M Mutant Human Anaplastic Lymphoma Kinase in Complex with 2-(5-(6-amino-5-((R)-1-(5-fluoro-2-(2H-1,2,3-triazol-2- yl)phenyl)ethoxy)pyridin-3-yl)-4-methylthiazol-2-yl)propane-1,2-diol
Method X-ray diffraction Resolution 2.23 Å Mutation Yes [1]
PDB Sequence
PNYCFAGKTS
1103
SISDLKEVPR
1113
KNITLIRGLG
1123
HGAFGEVYEG
1133
QVSPLQVAVK
1150

TLPEVCSEQD
1160
ELDFLMEALI
1170
ISKFNHQNIV
1180
RCIGVSLQSL
1190
PRFILMELMA
1200

GGDLKSFLRE
1210
TRPRPSQPSS
1220
LAMLDLLHVA
1230
RDIACGCQYL
1240
EENHFIHRDI
1250

AARNCLLTCP
1260
GPGRVAKIGD
1270
FGMARDIYRG
1286
GCAMLPVKWM
1296
PPEAFMEGIF
1306

TSKTDTWSFG
1316
VLLWEIFSLG
1326
YMPYPSKSNQ
1336
EVLEFVTSGG
1346
RMDPPKNCPG
1356

PVYRIMTQCW
1366
QHQPEDRPNF
1376
AIILERIEYC
1386
TQDPDVINTA
1396
LPIEYG
Residue
Distance (Å)
LEU1122
3.301
GLY1123
3.838
HIS1124
4.401
GLY1125
3.996
VAL1130
3.483
ALA1148
3.452
LYS1150
4.073
VAL1180
4.215
MET1196
3.875
GLU1197
2.890
LEU1198
3.864
MET1199
2.892
Residue
Distance (Å)
ALA1200
4.814
GLY1201
4.431
GLY1202
3.190
ASP1203
2.770
SER1206
3.658
ARG1253
3.281
ASN1254
3.350
CYS1255
4.429
LEU1256
3.523
GLY1269
2.856
ASP1270
3.146
PDB ID: 7R7R      Structure of Human Anaplastic Lymphoma Kinase Domain in complex with ((2~{R})-2-[5-[6-amino-5-[(1~{R})-1-[5-fluoro-2-(triazol-2-yl)phenyl]ethoxy]-3-pyridyl]-4-methyl-thiazol-2-yl]propane-1,2-diol)
Method X-ray diffraction Resolution 1.94 Å Mutation No [2]
PDB Sequence
NPNYCFAGKT
1102
SSISDLKEVP
1112
RKNITLIRGL
1122
GHGEVYEGQV
1135
PLQVAVKTLP
1153

EVCSEQDELD
1163
FLMEALIISK
1173
FNHQNIVRCI
1183
GVSLQSLPRF
1193
ILLELMAGGD
1203

LKSFLRETRP
1213
RPSQPSSLAM
1223
LDLLHVARDI
1233
ACGCQYLEEN
1243
HFIHRDIAAR
1253

NCLLTCPGPG
1263
RVAKIGDFGM
1273
ARDIYGGCAM
1290
LPVKWMPPEA
1300
FMEGIFTSKT
1310

DTWSFGVLLW
1320
EIFSLGYMPY
1330
PSKSNQEVLE
1340
FVTSGGRMDP
1350
PKNCPGPVYR
1360

IMTQCWQHQP
1370
EDRPNFAIIL
1380
ERIEYCTQDP
1390
DVINTALPIE
1400
Y
Residue
Distance (Å)
LEU1122
3.408
GLY1123
3.562
HIS1124
3.443
VAL1130
3.457
ALA1148
3.317
LYS1150
4.241
VAL1180
4.011
LEU1196
3.718
GLU1197
2.906
LEU1198
3.903
MET1199
2.973
Residue
Distance (Å)
ALA1200
4.660
GLY1201
4.464
GLY1202
3.303
ASP1203
2.743
SER1206
3.648
ARG1253
3.317
ASN1254
3.450
CYS1255
4.327
LEU1256
3.503
GLY1269
2.982
ASP1270
3.249
References  Top
REF 1 Design of potent and selective inhibitors to overcome clinical anaplastic lymphoma kinase mutations resistant to crizotinib. J Med Chem.> 2014 Feb 27;57(4):1170-87.
REF 2 Analysis of lorlatinib analogs reveals a roadmap for targeting diverse compound resistance mutations in ALK-positive lung cancer. Nat Cancer. 2022 Jun;3(6):710-722.

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