Disease Information

General Information of the Disease (ID: DIS00046)
Name
Brain cancer
ICD
ICD-11: 2A00
Resistance Map
Type(s) of Resistant Mechanism of This Disease with Structure Alteration
  ADTT: Aberration of the Drug's Therapeutic Target
  EADR: Epigenetic Alteration of DNA, RNA or Protein
  UAPP: Unusual Activation of Pro-survival Pathway
Drug Resistance Data Categorized by Drug
Approved Drug(s)
7 drug(s) in total
Click to Show/Hide the Full List of Drugs
Alectinib
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Key Molecule: ALK tyrosine kinase receptor (ALK) [1]
Resistant Disease Neuroblastoma [ICD-11: 2A00.11]
Resistant Drug Alectinib
 Drug Info 
Molecule Alteration Missense mutation
p.F1174L
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.75  Å
PDB: 3AOX
Mutant Type Structure Method: X-ray diffraction Resolution: 1.75  Å
PDB: 4FNW
   Download The Information of Sequence       Download The Structure File   
RMSD: 0.34
TM score: 0.99391
Amino acid change:
F1174L
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
G
-
M
-
1070
|
Q
-
M
-
E
-
L
-
Q
-
S
-
P
-
E
-
Y
-
K
-
1080
|
L
-
S
-
K
-
L
-
R
R
T
T
S
S
T
T
I
I
M
M
1090
|
T
T
D
D
Y
Y
N
N
P
P
N
N
Y
Y
C
S
F
F
A
A
1100
|
G
G
K
K
T
T
S
S
S
S
I
I
S
S
D
D
L
L
K
K
1110
|
E
E
V
V
P
P
R
R
K
K
N
N
I
I
T
T
L
L
I
I
1120
|
R
R
G
G
L
L
G
G
H
H
G
G
A
A
F
F
G
G
E
E
1130
|
V
V
Y
Y
E
E
G
G
Q
Q
V
V
S
S
G
G
M
M
P
P
1140
|
N
N
D
D
P
P
S
S
P
P
L
L
Q
Q
V
V
A
A
V
V
1150
|
K
K
T
T
L
L
P
P
E
E
V
V
C
C
S
S
E
E
Q
Q
1160
|
D
D
E
E
L
L
D
D
F
F
L
L
M
M
E
E
A
A
L
L
1170
|
I
I
I
I
S
S
K
K
F
L
N
N
H
H
Q
Q
N
N
I
I
1180
|
V
V
R
R
C
C
I
I
G
G
V
V
S
S
L
L
Q
Q
S
S
1190
|
L
L
P
P
R
R
F
F
I
I
L
L
L
L
E
E
L
L
M
M
1200
|
A
A
G
G
G
G
D
D
L
L
K
K
S
S
F
F
L
L
R
R
1210
|
E
E
T
T
R
R
P
P
R
R
P
P
S
S
Q
Q
P
P
S
S
1220
|
S
S
L
L
A
A
M
M
L
L
D
D
L
L
L
L
H
H
V
V
1230
|
A
A
R
R
D
D
I
I
A
A
C
C
G
G
C
C
Q
Q
Y
Y
1240
|
L
L
E
E
E
E
N
N
H
H
F
F
I
I
H
H
R
R
D
D
1250
|
I
I
A
A
A
A
R
R
N
N
C
C
L
L
L
L
T
T
C
C
1260
|
P
P
G
G
P
P
G
G
R
R
V
V
A
A
K
K
I
I
G
G
1270
|
D
D
F
F
G
G
M
M
A
A
R
R
D
D
I
I
Y
Y
R
R
1280
|
A
A
S
S
Y
Y
Y
Y
R
R
K
K
G
G
G
G
C
C
A
A
1290
|
M
M
L
L
P
P
V
V
K
K
W
W
M
M
P
P
P
P
E
E
1300
|
A
A
F
F
M
M
E
E
G
G
I
I
F
F
T
T
S
S
K
K
1310
|
T
T
D
D
T
T
W
W
S
S
F
F
G
G
V
V
L
L
L
L
1320
|
W
W
E
E
I
I
F
F
S
S
L
L
G
G
Y
Y
M
M
P
P
1330
|
Y
Y
P
P
S
S
K
K
S
S
N
N
Q
Q
E
E
V
V
L
L
1340
|
E
E
F
F
V
V
T
T
S
S
G
G
G
G
R
R
M
M
D
D
1350
|
P
P
P
P
K
K
N
N
C
C
P
P
G
G
P
P
V
V
Y
Y
1360
|
R
R
I
I
M
M
T
T
Q
Q
C
C
W
W
Q
Q
H
H
Q
Q
1370
|
P
P
E
E
D
D
R
R
P
P
N
N
F
F
A
A
I
I
I
I
1380
|
L
L
E
E
R
R
I
I
E
E
Y
Y
C
C
T
T
Q
Q
D
D
1390
|
P
P
D
D
V
V
I
I
N
N
T
T
A
A
L
L
P
P
I
I
1400
|
E
E
Y
Y
G
G
P
P
L
L
V
V
E
E
E
E
E
E
E
E
1410
|
K
K
V
-
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell invasion Activation hsa05200
Cell migration Activation hsa04670
Cell proliferation Activation hsa05200
In Vitro Model NBLW cells Brain Homo sapiens (Human) CVCL_VJ90
NBLW-R cells Brain Homo sapiens (Human) CVCL_VJ91
Experiment for
Molecule Alteration		 Sangersequencing assay; Targeted deep sequencing assay
Experiment for
Drug Resistance		 Array CGH assay
Mechanism Description Analysis of the sensitivity of NBLW and NBLW-R cells to a panel of ALk inhibitors (TAE-684, Crizotinib, Alectinib and Lorlatinib) revealed differences between the paired cell lines, and overall NBLW-R cells with the F1174L mutation were more resistant to ALk inhibitor induced apoptosis compared with NBLW cells.
Azacitidine
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Oxalosuccinate decarboxylase (IDH1) [2]
Sensitive Disease FGFR-tacc positive glioblastoma [ICD-11: 2A00.01]
Sensitive Drug Azacitidine
 Drug Info 
Molecule Alteration Missense mutation
p.R132H (c.395G>A)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.65  Å
PDB: 6BKX
Mutant Type Structure Method: X-ray diffraction Resolution: 1.88  Å
PDB: 4UMX
   Download The Information of Sequence       Download The Structure File   
RMSD: 3.46
TM score: 0.85834
Amino acid change:
R132H
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
M
M
S
S
K
K
K
K
I
I
S
S
G
G
G
G
S
S
10
|
V
V
V
V
E
E
M
M
Q
Q
G
G
D
D
E
E
M
M
T
T
20
|
R
R
I
I
I
I
W
W
E
E
L
L
I
I
K
K
E
E
K
K
30
|
L
L
I
I
F
F
P
P
Y
Y
V
V
E
E
L
L
D
D
L
L
40
|
H
H
S
S
Y
Y
D
D
L
L
G
G
I
I
E
E
N
N
R
R
50
|
D
D
A
A
T
T
N
N
D
D
Q
Q
V
V
T
T
K
K
D
D
60
|
A
A
A
A
E
E
A
A
I
I
K
K
K
K
H
H
N
N
V
V
70
|
G
G
V
V
K
K
C
C
A
A
T
T
I
I
T
T
P
P
D
D
80
|
E
E
K
K
R
R
V
V
E
E
E
E
F
F
K
K
L
L
K
K
90
|
Q
Q
M
M
W
W
K
K
S
S
P
P
N
N
G
G
T
T
I
I
100
|
R
R
N
N
I
I
L
L
G
G
G
G
T
T
V
V
F
F
R
R
110
|
E
E
A
A
I
I
I
I
C
C
K
K
N
N
I
I
P
P
R
R
120
|
L
L
V
V
S
S
G
G
W
W
V
V
K
K
P
P
I
I
I
I
130
|
I
I
G
G
R
H
H
H
A
A
Y
Y
G
G
D
D
Q
Q
Y
Y
140
|
R
R
A
A
T
T
D
D
F
F
V
V
V
V
P
P
G
G
P
P
150
|
G
G
K
K
V
V
E
E
I
I
T
T
Y
Y
T
T
P
P
S
S
160
|
D
D
G
G
T
T
Q
Q
K
K
V
V
T
T
Y
Y
L
L
V
V
170
|
H
H
N
N
F
F
E
E
E
E
G
G
G
G
G
G
V
V
A
A
180
|
M
M
G
G
M
M
Y
Y
N
N
Q
Q
D
D
K
K
S
S
I
I
190
|
E
E
D
D
F
F
A
A
H
H
S
S
S
S
F
F
Q
Q
M
M
200
|
A
A
L
L
S
S
K
K
G
G
W
W
P
P
L
L
Y
Y
L
L
210
|
S
S
T
T
K
K
N
N
T
T
I
I
L
L
K
K
K
K
Y
Y
220
|
D
D
G
G
R
R
F
F
K
K
D
D
I
I
F
F
Q
Q
E
E
230
|
I
I
Y
Y
D
D
K
K
Q
Q
Y
Y
K
K
S
S
Q
Q
F
F
240
|
E
E
A
A
Q
Q
K
K
I
I
W
W
Y
Y
E
E
H
H
R
R
250
|
L
L
I
I
D
D
D
D
M
M
V
V
A
A
Q
Q
A
A
M
M
260
|
K
K
S
S
E
E
G
G
G
G
F
F
I
I
W
W
A
A
C
C
270
|
K
K
N
N
Y
Y
D
D
G
G
D
D
V
V
Q
Q
S
S
D
D
280
|
S
S
V
V
A
A
Q
Q
G
G
Y
Y
G
G
S
S
L
L
G
G
290
|
M
M
M
M
T
T
S
S
V
V
L
L
V
V
C
C
P
P
D
D
300
|
G
G
K
K
T
T
V
V
E
E
A
A
E
E
A
A
A
A
H
H
310
|
G
G
T
T
V
V
T
T
R
R
H
H
Y
Y
R
R
M
M
Y
Y
320
|
Q
Q
K
K
G
G
Q
Q
E
E
T
T
S
S
T
T
N
N
P
P
330
|
I
I
A
A
S
S
I
I
F
F
A
A
W
W
T
T
R
R
G
G
340
|
L
L
A
A
H
H
R
R
A
A
K
K
L
L
D
D
N
N
N
N
350
|
K
K
E
E
L
L
A
A
F
F
F
F
A
A
N
N
A
A
L
L
360
|
E
E
E
E
V
V
S
S
I
I
E
E
T
T
I
I
E
E
A
A
370
|
G
G
F
F
M
M
T
T
K
K
D
D
L
L
A
A
A
A
C
C
380
|
I
I
K
K
G
G
L
L
P
P
N
N
V
V
Q
Q
R
R
S
S
390
|
D
D
Y
Y
L
L
N
N
T
T
F
F
E
E
F
F
M
M
D
D
400
|
K
K
L
L
G
G
E
E
N
N
L
L
K
K
I
I
K
K
L
L
410
|
A
A
Q
Q
A
A
K
K
L
L
S
S
L
L
E
E
H
H
H
H
420
|
H
H
H
H
H
H
H
H
H
H
H
H
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
In Vitro Model Brain N.A.
In Vivo Model Female athymic nude mouse (NCI-Frederick) model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 Tumor volume measurement assay
Bevacizumab
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Oxalosuccinate decarboxylase (IDH1) [3]
Sensitive Disease Brain glioma [ICD-11: 2A00.0]
Sensitive Drug Bevacizumab
 Drug Info 
Molecule Alteration Missense mutation
p.R132C (c.394C>T)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.93  Å
PDB: 5GIR
Mutant Type Structure Method: X-ray diffraction Resolution: 2.20  Å
PDB: 6IO0
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.64
TM score: 0.30204
Amino acid change:
R132C
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
-
M
-
S
-
K
-
K
-
I
-
S
-
G
-
G
-
S
10
|
-
V
-
V
-
E
-
M
-
Q
-
G
-
D
-
E
-
M
-
T
20
|
-
R
-
I
-
I
-
W
-
E
-
L
-
I
-
K
-
E
-
K
30
|
-
L
-
I
-
F
-
P
-
Y
-
V
-
E
-
L
-
D
-
L
40
|
-
H
-
S
-
Y
-
D
-
L
-
G
-
I
-
E
-
N
-
R
50
|
-
D
-
A
-
T
-
N
-
D
-
Q
-
V
-
T
-
K
-
D
60
|
-
A
-
A
-
E
-
A
-
I
-
K
-
K
-
H
-
N
-
V
70
|
-
G
-
V
-
K
-
C
-
A
-
T
-
I
-
T
-
P
-
D
80
|
-
E
-
K
-
R
-
V
-
E
-
E
-
F
-
K
-
L
-
K
90
|
-
Q
-
M
-
W
-
K
-
S
-
P
-
N
-
G
-
T
-
I
100
|
-
R
-
N
-
I
-
L
-
G
-
G
-
T
-
V
-
F
-
R
110
|
-
E
-
A
-
I
-
I
-
C
-
K
-
N
-
I
-
P
-
R
120
|
-
L
-
V
-
S
-
G
-
W
-
V
K
K
P
P
I
I
I
I
130
|
I
I
G
G
S
C
H
H
A
A
Y
Y
G
G
D
D
-
Q
-
Y
140
|
-
R
-
A
-
T
-
D
-
F
-
V
-
V
-
P
-
G
-
P
150
|
-
G
-
K
-
V
-
E
-
I
-
T
-
Y
-
T
-
P
-
S
160
|
-
D
-
G
-
T
-
Q
-
K
-
V
-
T
-
Y
-
L
-
V
170
|
-
H
-
N
-
F
-
E
-
E
-
G
-
G
-
G
-
V
-
A
180
|
-
M
-
G
-
M
-
Y
-
N
-
Q
-
D
-
K
-
S
-
I
190
|
-
E
-
D
-
F
-
A
-
H
-
S
-
S
-
F
-
Q
-
M
200
|
-
A
-
L
-
S
-
K
-
G
-
W
-
P
-
L
-
Y
-
L
210
|
-
S
-
T
-
K
-
N
-
T
-
I
-
L
-
K
-
K
-
Y
220
|
-
D
-
G
-
R
-
F
-
K
-
D
-
I
-
F
-
Q
-
E
230
|
-
I
-
Y
-
D
-
K
-
Q
-
Y
-
K
-
S
-
Q
-
F
240
|
-
E
-
A
-
Q
-
K
-
I
-
W
-
Y
-
E
-
H
-
R
250
|
-
L
-
I
-
D
-
D
-
M
-
V
-
A
-
Q
-
A
-
M
260
|
-
K
-
S
-
E
-
G
-
G
-
F
-
I
-
W
-
A
-
C
270
|
-
K
-
N
-
Y
-
D
-
G
-
D
-
V
-
Q
-
S
-
D
280
|
-
S
-
V
-
A
-
Q
-
G
-
Y
-
G
-
S
-
L
-
G
290
|
-
M
-
M
-
T
-
S
-
V
-
L
-
V
-
C
-
P
-
D
300
|
-
G
-
K
-
T
-
V
-
E
-
A
-
E
-
A
-
A
-
H
310
|
-
G
-
T
-
V
-
T
-
R
-
H
-
Y
-
R
-
M
-
Y
320
|
-
Q
-
K
-
G
-
Q
-
E
-
T
-
S
-
T
-
N
-
P
330
|
-
I
-
A
-
S
-
I
-
F
-
A
-
W
-
T
-
R
-
G
340
|
-
L
-
A
-
H
-
R
-
A
-
K
-
L
-
D
-
N
-
N
350
|
-
K
-
E
-
L
-
A
-
F
-
F
-
A
-
N
-
A
-
L
360
|
-
E
-
E
-
V
-
S
-
I
-
E
-
T
-
I
-
E
-
A
370
|
-
G
-
F
-
M
-
T
-
K
-
D
-
L
-
A
-
A
-
C
380
|
-
I
-
K
-
G
-
L
-
P
-
N
-
V
-
Q
-
R
-
S
390
|
-
D
-
Y
-
L
-
N
-
T
-
F
-
E
-
F
-
M
-
D
400
|
-
K
-
L
-
G
-
E
-
N
-
L
-
K
-
I
-
K
-
L
410
|
-
A
-
Q
-
A
-
K
-
L
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
In Vitro Model Brain N.A.
Mechanism Description The missense mutation p.R132C (c.394C>T) in gene IDH1 cause the sensitivity of Bevacizumab by aberration of the drug's therapeutic target
Crizotinib
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Key Molecule: ALK tyrosine kinase receptor (ALK) [1]
Resistant Disease Neuroblastoma [ICD-11: 2A00.11]
Resistant Drug Crizotinib
 Drug Info 
Molecule Alteration Missense mutation
p.F1174L
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.75  Å
PDB: 3AOX
Mutant Type Structure Method: X-ray diffraction Resolution: 1.75  Å
PDB: 4FNW
   Download The Information of Sequence       Download The Structure File   
RMSD: 0.34
TM score: 0.99391
Amino acid change:
F1174L
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
G
-
M
-
1070
|
Q
-
M
-
E
-
L
-
Q
-
S
-
P
-
E
-
Y
-
K
-
1080
|
L
-
S
-
K
-
L
-
R
R
T
T
S
S
T
T
I
I
M
M
1090
|
T
T
D
D
Y
Y
N
N
P
P
N
N
Y
Y
C
S
F
F
A
A
1100
|
G
G
K
K
T
T
S
S
S
S
I
I
S
S
D
D
L
L
K
K
1110
|
E
E
V
V
P
P
R
R
K
K
N
N
I
I
T
T
L
L
I
I
1120
|
R
R
G
G
L
L
G
G
H
H
G
G
A
A
F
F
G
G
E
E
1130
|
V
V
Y
Y
E
E
G
G
Q
Q
V
V
S
S
G
G
M
M
P
P
1140
|
N
N
D
D
P
P
S
S
P
P
L
L
Q
Q
V
V
A
A
V
V
1150
|
K
K
T
T
L
L
P
P
E
E
V
V
C
C
S
S
E
E
Q
Q
1160
|
D
D
E
E
L
L
D
D
F
F
L
L
M
M
E
E
A
A
L
L
1170
|
I
I
I
I
S
S
K
K
F
L
N
N
H
H
Q
Q
N
N
I
I
1180
|
V
V
R
R
C
C
I
I
G
G
V
V
S
S
L
L
Q
Q
S
S
1190
|
L
L
P
P
R
R
F
F
I
I
L
L
L
L
E
E
L
L
M
M
1200
|
A
A
G
G
G
G
D
D
L
L
K
K
S
S
F
F
L
L
R
R
1210
|
E
E
T
T
R
R
P
P
R
R
P
P
S
S
Q
Q
P
P
S
S
1220
|
S
S
L
L
A
A
M
M
L
L
D
D
L
L
L
L
H
H
V
V
1230
|
A
A
R
R
D
D
I
I
A
A
C
C
G
G
C
C
Q
Q
Y
Y
1240
|
L
L
E
E
E
E
N
N
H
H
F
F
I
I
H
H
R
R
D
D
1250
|
I
I
A
A
A
A
R
R
N
N
C
C
L
L
L
L
T
T
C
C
1260
|
P
P
G
G
P
P
G
G
R
R
V
V
A
A
K
K
I
I
G
G
1270
|
D
D
F
F
G
G
M
M
A
A
R
R
D
D
I
I
Y
Y
R
R
1280
|
A
A
S
S
Y
Y
Y
Y
R
R
K
K
G
G
G
G
C
C
A
A
1290
|
M
M
L
L
P
P
V
V
K
K
W
W
M
M
P
P
P
P
E
E
1300
|
A
A
F
F
M
M
E
E
G
G
I
I
F
F
T
T
S
S
K
K
1310
|
T
T
D
D
T
T
W
W
S
S
F
F
G
G
V
V
L
L
L
L
1320
|
W
W
E
E
I
I
F
F
S
S
L
L
G
G
Y
Y
M
M
P
P
1330
|
Y
Y
P
P
S
S
K
K
S
S
N
N
Q
Q
E
E
V
V
L
L
1340
|
E
E
F
F
V
V
T
T
S
S
G
G
G
G
R
R
M
M
D
D
1350
|
P
P
P
P
K
K
N
N
C
C
P
P
G
G
P
P
V
V
Y
Y
1360
|
R
R
I
I
M
M
T
T
Q
Q
C
C
W
W
Q
Q
H
H
Q
Q
1370
|
P
P
E
E
D
D
R
R
P
P
N
N
F
F
A
A
I
I
I
I
1380
|
L
L
E
E
R
R
I
I
E
E
Y
Y
C
C
T
T
Q
Q
D
D
1390
|
P
P
D
D
V
V
I
I
N
N
T
T
A
A
L
L
P
P
I
I
1400
|
E
E
Y
Y
G
G
P
P
L
L
V
V
E
E
E
E
E
E
E
E
1410
|
K
K
V
-
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell invasion Activation hsa05200
Cell migration Activation hsa04670
Cell proliferation Activation hsa05200
In Vitro Model NBLW cells Brain Homo sapiens (Human) CVCL_VJ90
NBLW-R cells Brain Homo sapiens (Human) CVCL_VJ91
Experiment for
Molecule Alteration		 Sangersequencing assay; Targeted deep sequencing assay
Experiment for
Drug Resistance		 Array CGH assay
Mechanism Description Analysis of the sensitivity of NBLW and NBLW-R cells to a panel of ALk inhibitors (TAE-684, Crizotinib, Alectinib and Lorlatinib) revealed differences between the paired cell lines, and overall NBLW-R cells with the F1174L mutation were more resistant to ALk inhibitor induced apoptosis compared with NBLW cells.
  Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
Key Molecule: ALK tyrosine kinase receptor (ALK) [4]
Resistant Disease Neuroblastoma [ICD-11: 2A00.11]
Resistant Drug Crizotinib
 Drug Info 
Molecule Alteration Missense mutation
p.F1174L
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.75  Å
PDB: 3AOX
Mutant Type Structure Method: X-ray diffraction Resolution: 1.75  Å
PDB: 4FNW
   Download The Information of Sequence       Download The Structure File   
RMSD: 0.34
TM score: 0.99391
Amino acid change:
F1174L
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
G
-
M
-
1070
|
Q
-
M
-
E
-
L
-
Q
-
S
-
P
-
E
-
Y
-
K
-
1080
|
L
-
S
-
K
-
L
-
R
R
T
T
S
S
T
T
I
I
M
M
1090
|
T
T
D
D
Y
Y
N
N
P
P
N
N
Y
Y
C
S
F
F
A
A
1100
|
G
G
K
K
T
T
S
S
S
S
I
I
S
S
D
D
L
L
K
K
1110
|
E
E
V
V
P
P
R
R
K
K
N
N
I
I
T
T
L
L
I
I
1120
|
R
R
G
G
L
L
G
G
H
H
G
G
A
A
F
F
G
G
E
E
1130
|
V
V
Y
Y
E
E
G
G
Q
Q
V
V
S
S
G
G
M
M
P
P
1140
|
N
N
D
D
P
P
S
S
P
P
L
L
Q
Q
V
V
A
A
V
V
1150
|
K
K
T
T
L
L
P
P
E
E
V
V
C
C
S
S
E
E
Q
Q
1160
|
D
D
E
E
L
L
D
D
F
F
L
L
M
M
E
E
A
A
L
L
1170
|
I
I
I
I
S
S
K
K
F
L
N
N
H
H
Q
Q
N
N
I
I
1180
|
V
V
R
R
C
C
I
I
G
G
V
V
S
S
L
L
Q
Q
S
S
1190
|
L
L
P
P
R
R
F
F
I
I
L
L
L
L
E
E
L
L
M
M
1200
|
A
A
G
G
G
G
D
D
L
L
K
K
S
S
F
F
L
L
R
R
1210
|
E
E
T
T
R
R
P
P
R
R
P
P
S
S
Q
Q
P
P
S
S
1220
|
S
S
L
L
A
A
M
M
L
L
D
D
L
L
L
L
H
H
V
V
1230
|
A
A
R
R
D
D
I
I
A
A
C
C
G
G
C
C
Q
Q
Y
Y
1240
|
L
L
E
E
E
E
N
N
H
H
F
F
I
I
H
H
R
R
D
D
1250
|
I
I
A
A
A
A
R
R
N
N
C
C
L
L
L
L
T
T
C
C
1260
|
P
P
G
G
P
P
G
G
R
R
V
V
A
A
K
K
I
I
G
G
1270
|
D
D
F
F
G
G
M
M
A
A
R
R
D
D
I
I
Y
Y
R
R
1280
|
A
A
S
S
Y
Y
Y
Y
R
R
K
K
G
G
G
G
C
C
A
A
1290
|
M
M
L
L
P
P
V
V
K
K
W
W
M
M
P
P
P
P
E
E
1300
|
A
A
F
F
M
M
E
E
G
G
I
I
F
F
T
T
S
S
K
K
1310
|
T
T
D
D
T
T
W
W
S
S
F
F
G
G
V
V
L
L
L
L
1320
|
W
W
E
E
I
I
F
F
S
S
L
L
G
G
Y
Y
M
M
P
P
1330
|
Y
Y
P
P
S
S
K
K
S
S
N
N
Q
Q
E
E
V
V
L
L
1340
|
E
E
F
F
V
V
T
T
S
S
G
G
G
G
R
R
M
M
D
D
1350
|
P
P
P
P
K
K
N
N
C
C
P
P
G
G
P
P
V
V
Y
Y
1360
|
R
R
I
I
M
M
T
T
Q
Q
C
C
W
W
Q
Q
H
H
Q
Q
1370
|
P
P
E
E
D
D
R
R
P
P
N
N
F
F
A
A
I
I
I
I
1380
|
L
L
E
E
R
R
I
I
E
E
Y
Y
C
C
T
T
Q
Q
D
D
1390
|
P
P
D
D
V
V
I
I
N
N
T
T
A
A
L
L
P
P
I
I
1400
|
E
E
Y
Y
G
G
P
P
L
L
V
V
E
E
E
E
E
E
E
E
1410
|
K
K
V
-
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation ALK signaling pathway Activation hsa05200
Cell apoptosis Inhibition hsa04210
Cell invasion Activation hsa05200
In Vitro Model NCI-H3122 cells Lung Homo sapiens (Human) CVCL_5160
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Direct sequencing assay
Experiment for
Drug Resistance		 MTS assay
Mechanism Description There is a C to G mutation (asterix) in codon 3522 in exon 23 resulting in the F1174L mutation. When present in cis with an ALk translocation, this mutation (also detected in neuroblastomas) causes an increase in ALk phosphorylation, cell growth and downstream signaling. Furthermore, the F1174L mutation inhibits crizotinib mediated downregulation of ALk signaling and blocks apoptosis in RANBP2-ALk Ba/F3 cells.
Dabrafenib/Trametinib
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [5]
Sensitive Disease FGFR-tacc positive glioblastoma [ICD-11: 2A00.01]
Sensitive Drug Dabrafenib/Trametinib
 Drug Info 
Molecule Alteration Missense mutation
p.V600E (c.1799T>A)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 2.55  Å
PDB: 4E26
Mutant Type Structure Method: X-ray diffraction Resolution: 3.20  Å
PDB: 4G9R
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.53
TM score: 0.95765
Amino acid change:
V600E
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
420
|
M
M
D
D
R
R
G
G
S
S
H
H
H
H
H
H
H
H
H
H
430
|
H
H
G
G
S
S
E
E
D
D
R
R
N
N
R
R
M
M
K
K
440
|
T
T
L
L
G
G
R
R
R
R
D
D
S
S
S
S
D
D
D
D
450
|
W
W
E
E
I
I
P
P
D
D
G
G
Q
Q
I
I
T
T
V
V
460
|
G
G
Q
Q
R
R
I
I
G
G
S
S
G
G
S
S
F
F
G
G
470
|
T
T
V
V
Y
Y
K
K
G
G
K
K
W
W
H
H
G
G
D
D
480
|
V
V
A
A
V
V
K
K
M
M
L
L
N
N
V
V
T
T
A
A
490
|
P
P
T
T
P
P
Q
Q
Q
Q
L
L
Q
Q
A
A
F
F
K
K
500
|
N
N
E
E
V
V
G
G
V
V
L
L
R
R
K
K
T
T
R
R
510
|
H
H
V
V
N
N
I
I
L
L
L
L
F
F
M
M
G
G
Y
Y
520
|
S
S
T
T
K
K
P
P
Q
Q
L
L
A
A
I
I
V
V
T
T
530
|
Q
Q
W
W
C
C
E
E
G
G
S
S
S
S
L
L
Y
Y
H
H
540
|
H
H
L
L
H
H
I
I
I
I
E
E
T
T
K
K
F
F
E
E
550
|
M
M
I
I
K
K
L
L
I
I
D
D
I
I
A
A
R
R
Q
Q
560
|
T
T
A
A
Q
Q
G
G
M
M
D
D
Y
Y
L
L
H
H
A
A
570
|
K
K
S
S
I
I
I
I
H
H
R
R
D
D
L
L
K
K
S
S
580
|
N
N
N
N
I
I
F
F
L
L
H
H
E
E
D
D
L
L
T
T
590
|
V
V
K
K
I
I
G
G
D
D
F
F
G
G
L
L
A
A
T
T
600
|
V
E
K
K
S
S
R
R
W
W
S
S
G
G
S
S
H
H
Q
Q
610
|
F
F
E
E
Q
Q
L
L
S
S
G
G
S
S
I
I
L
L
W
W
620
|
M
M
A
A
P
P
E
E
V
V
I
I
R
R
M
M
Q
Q
D
D
630
|
K
K
N
N
P
P
Y
Y
S
S
F
F
Q
Q
S
S
D
D
V
V
640
|
Y
Y
A
A
F
F
G
G
I
I
V
V
L
L
Y
Y
E
E
L
L
650
|
M
M
T
T
G
G
Q
Q
L
L
P
P
Y
Y
S
S
N
N
I
I
660
|
N
N
N
N
R
R
D
D
Q
Q
I
I
I
I
F
F
M
M
V
V
670
|
G
G
R
R
G
G
Y
Y
L
L
S
S
P
P
D
D
L
L
S
S
680
|
K
K
V
V
R
R
S
S
N
N
C
C
P
P
K
K
A
A
M
M
690
|
K
K
R
R
L
L
M
M
A
A
E
E
C
C
L
L
K
K
K
K
700
|
K
K
R
R
D
D
E
E
R
R
P
P
L
L
F
F
P
P
Q
Q
710
|
I
I
L
L
A
A
S
S
I
I
E
E
L
L
L
L
A
A
R
R
720
|
S
S
L
L
P
P
K
K
I
I
H
H
R
R
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [5]
Sensitive Disease Pleomorphic xanthoastrocytoma [ICD-11: 2A00.0Y]
Sensitive Drug Dabrafenib/Trametinib
 Drug Info 
Molecule Alteration Missense mutation
p.V600E (c.1799T>A)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 2.55  Å
PDB: 4E26
Mutant Type Structure Method: X-ray diffraction Resolution: 3.20  Å
PDB: 4G9R
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.53
TM score: 0.95765
Amino acid change:
V600E
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
420
|
M
M
D
D
R
R
G
G
S
S
H
H
H
H
H
H
H
H
H
H
430
|
H
H
G
G
S
S
E
E
D
D
R
R
N
N
R
R
M
M
K
K
440
|
T
T
L
L
G
G
R
R
R
R
D
D
S
S
S
S
D
D
D
D
450
|
W
W
E
E
I
I
P
P
D
D
G
G
Q
Q
I
I
T
T
V
V
460
|
G
G
Q
Q
R
R
I
I
G
G
S
S
G
G
S
S
F
F
G
G
470
|
T
T
V
V
Y
Y
K
K
G
G
K
K
W
W
H
H
G
G
D
D
480
|
V
V
A
A
V
V
K
K
M
M
L
L
N
N
V
V
T
T
A
A
490
|
P
P
T
T
P
P
Q
Q
Q
Q
L
L
Q
Q
A
A
F
F
K
K
500
|
N
N
E
E
V
V
G
G
V
V
L
L
R
R
K
K
T
T
R
R
510
|
H
H
V
V
N
N
I
I
L
L
L
L
F
F
M
M
G
G
Y
Y
520
|
S
S
T
T
K
K
P
P
Q
Q
L
L
A
A
I
I
V
V
T
T
530
|
Q
Q
W
W
C
C
E
E
G
G
S
S
S
S
L
L
Y
Y
H
H
540
|
H
H
L
L
H
H
I
I
I
I
E
E
T
T
K
K
F
F
E
E
550
|
M
M
I
I
K
K
L
L
I
I
D
D
I
I
A
A
R
R
Q
Q
560
|
T
T
A
A
Q
Q
G
G
M
M
D
D
Y
Y
L
L
H
H
A
A
570
|
K
K
S
S
I
I
I
I
H
H
R
R
D
D
L
L
K
K
S
S
580
|
N
N
N
N
I
I
F
F
L
L
H
H
E
E
D
D
L
L
T
T
590
|
V
V
K
K
I
I
G
G
D
D
F
F
G
G
L
L
A
A
T
T
600
|
V
E
K
K
S
S
R
R
W
W
S
S
G
G
S
S
H
H
Q
Q
610
|
F
F
E
E
Q
Q
L
L
S
S
G
G
S
S
I
I
L
L
W
W
620
|
M
M
A
A
P
P
E
E
V
V
I
I
R
R
M
M
Q
Q
D
D
630
|
K
K
N
N
P
P
Y
Y
S
S
F
F
Q
Q
S
S
D
D
V
V
640
|
Y
Y
A
A
F
F
G
G
I
I
V
V
L
L
Y
Y
E
E
L
L
650
|
M
M
T
T
G
G
Q
Q
L
L
P
P
Y
Y
S
S
N
N
I
I
660
|
N
N
N
N
R
R
D
D
Q
Q
I
I
I
I
F
F
M
M
V
V
670
|
G
G
R
R
G
G
Y
Y
L
L
S
S
P
P
D
D
L
L
S
S
680
|
K
K
V
V
R
R
S
S
N
N
C
C
P
P
K
K
A
A
M
M
690
|
K
K
R
R
L
L
M
M
A
A
E
E
C
C
L
L
K
K
K
K
700
|
K
K
R
R
D
D
E
E
R
R
P
P
L
L
F
F
P
P
Q
Q
710
|
I
I
L
L
A
A
S
S
I
I
E
E
L
L
L
L
A
A
R
R
720
|
S
S
L
L
P
P
K
K
I
I
H
H
R
R
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation ERK signaling pathway Inhibition hsa04210
In Vitro Model Brain N.A.
Lorlatinib
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Key Molecule: ALK tyrosine kinase receptor (ALK) [1]
Resistant Disease Neuroblastoma [ICD-11: 2A00.11]
Resistant Drug Lorlatinib
 Drug Info 
Molecule Alteration Missense mutation
p.F1174L
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.75  Å
PDB: 3AOX
Mutant Type Structure Method: X-ray diffraction Resolution: 1.75  Å
PDB: 4FNW
   Download The Information of Sequence       Download The Structure File   
RMSD: 0.34
TM score: 0.99391
Amino acid change:
F1174L
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
G
-
M
-
1070
|
Q
-
M
-
E
-
L
-
Q
-
S
-
P
-
E
-
Y
-
K
-
1080
|
L
-
S
-
K
-
L
-
R
R
T
T
S
S
T
T
I
I
M
M
1090
|
T
T
D
D
Y
Y
N
N
P
P
N
N
Y
Y
C
S
F
F
A
A
1100
|
G
G
K
K
T
T
S
S
S
S
I
I
S
S
D
D
L
L
K
K
1110
|
E
E
V
V
P
P
R
R
K
K
N
N
I
I
T
T
L
L
I
I
1120
|
R
R
G
G
L
L
G
G
H
H
G
G
A
A
F
F
G
G
E
E
1130
|
V
V
Y
Y
E
E
G
G
Q
Q
V
V
S
S
G
G
M
M
P
P
1140
|
N
N
D
D
P
P
S
S
P
P
L
L
Q
Q
V
V
A
A
V
V
1150
|
K
K
T
T
L
L
P
P
E
E
V
V
C
C
S
S
E
E
Q
Q
1160
|
D
D
E
E
L
L
D
D
F
F
L
L
M
M
E
E
A
A
L
L
1170
|
I
I
I
I
S
S
K
K
F
L
N
N
H
H
Q
Q
N
N
I
I
1180
|
V
V
R
R
C
C
I
I
G
G
V
V
S
S
L
L
Q
Q
S
S
1190
|
L
L
P
P
R
R
F
F
I
I
L
L
L
L
E
E
L
L
M
M
1200
|
A
A
G
G
G
G
D
D
L
L
K
K
S
S
F
F
L
L
R
R
1210
|
E
E
T
T
R
R
P
P
R
R
P
P
S
S
Q
Q
P
P
S
S
1220
|
S
S
L
L
A
A
M
M
L
L
D
D
L
L
L
L
H
H
V
V
1230
|
A
A
R
R
D
D
I
I
A
A
C
C
G
G
C
C
Q
Q
Y
Y
1240
|
L
L
E
E
E
E
N
N
H
H
F
F
I
I
H
H
R
R
D
D
1250
|
I
I
A
A
A
A
R
R
N
N
C
C
L
L
L
L
T
T
C
C
1260
|
P
P
G
G
P
P
G
G
R
R
V
V
A
A
K
K
I
I
G
G
1270
|
D
D
F
F
G
G
M
M
A
A
R
R
D
D
I
I
Y
Y
R
R
1280
|
A
A
S
S
Y
Y
Y
Y
R
R
K
K
G
G
G
G
C
C
A
A
1290
|
M
M
L
L
P
P
V
V
K
K
W
W
M
M
P
P
P
P
E
E
1300
|
A
A
F
F
M
M
E
E
G
G
I
I
F
F
T
T
S
S
K
K
1310
|
T
T
D
D
T
T
W
W
S
S
F
F
G
G
V
V
L
L
L
L
1320
|
W
W
E
E
I
I
F
F
S
S
L
L
G
G
Y
Y
M
M
P
P
1330
|
Y
Y
P
P
S
S
K
K
S
S
N
N
Q
Q
E
E
V
V
L
L
1340
|
E
E
F
F
V
V
T
T
S
S
G
G
G
G
R
R
M
M
D
D
1350
|
P
P
P
P
K
K
N
N
C
C
P
P
G
G
P
P
V
V
Y
Y
1360
|
R
R
I
I
M
M
T
T
Q
Q
C
C
W
W
Q
Q
H
H
Q
Q
1370
|
P
P
E
E
D
D
R
R
P
P
N
N
F
F
A
A
I
I
I
I
1380
|
L
L
E
E
R
R
I
I
E
E
Y
Y
C
C
T
T
Q
Q
D
D
1390
|
P
P
D
D
V
V
I
I
N
N
T
T
A
A
L
L
P
P
I
I
1400
|
E
E
Y
Y
G
G
P
P
L
L
V
V
E
E
E
E
E
E
E
E
1410
|
K
K
V
-
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell invasion Activation hsa05200
Cell migration Activation hsa04670
Cell proliferation Activation hsa05200
In Vitro Model NBLW cells Brain Homo sapiens (Human) CVCL_VJ90
NBLW-R cells Brain Homo sapiens (Human) CVCL_VJ91
Experiment for
Molecule Alteration		 Sangersequencing assay; Targeted deep sequencing assay
Experiment for
Drug Resistance		 Array CGH assay
Mechanism Description Analysis of the sensitivity of NBLW and NBLW-R cells to a panel of ALk inhibitors (TAE-684, Crizotinib, Alectinib and Lorlatinib) revealed differences between the paired cell lines, and overall NBLW-R cells with the F1174L mutation were more resistant to ALk inhibitor induced apoptosis compared with NBLW cells.
Talazoparib
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
Key Molecule: Oxalosuccinate decarboxylase (IDH1) [6]
Sensitive Disease Brain glioma [ICD-11: 2A00.0]
Sensitive Drug Talazoparib
 Drug Info 
Molecule Alteration Missense mutation
p.R132H (c.395G>A)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.65  Å
PDB: 6BKX
Mutant Type Structure Method: X-ray diffraction Resolution: 1.88  Å
PDB: 4UMX
   Download The Information of Sequence       Download The Structure File   
RMSD: 3.46
TM score: 0.85834
Amino acid change:
R132H
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
M
M
S
S
K
K
K
K
I
I
S
S
G
G
G
G
S
S
10
|
V
V
V
V
E
E
M
M
Q
Q
G
G
D
D
E
E
M
M
T
T
20
|
R
R
I
I
I
I
W
W
E
E
L
L
I
I
K
K
E
E
K
K
30
|
L
L
I
I
F
F
P
P
Y
Y
V
V
E
E
L
L
D
D
L
L
40
|
H
H
S
S
Y
Y
D
D
L
L
G
G
I
I
E
E
N
N
R
R
50
|
D
D
A
A
T
T
N
N
D
D
Q
Q
V
V
T
T
K
K
D
D
60
|
A
A
A
A
E
E
A
A
I
I
K
K
K
K
H
H
N
N
V
V
70
|
G
G
V
V
K
K
C
C
A
A
T
T
I
I
T
T
P
P
D
D
80
|
E
E
K
K
R
R
V
V
E
E
E
E
F
F
K
K
L
L
K
K
90
|
Q
Q
M
M
W
W
K
K
S
S
P
P
N
N
G
G
T
T
I
I
100
|
R
R
N
N
I
I
L
L
G
G
G
G
T
T
V
V
F
F
R
R
110
|
E
E
A
A
I
I
I
I
C
C
K
K
N
N
I
I
P
P
R
R
120
|
L
L
V
V
S
S
G
G
W
W
V
V
K
K
P
P
I
I
I
I
130
|
I
I
G
G
R
H
H
H
A
A
Y
Y
G
G
D
D
Q
Q
Y
Y
140
|
R
R
A
A
T
T
D
D
F
F
V
V
V
V
P
P
G
G
P
P
150
|
G
G
K
K
V
V
E
E
I
I
T
T
Y
Y
T
T
P
P
S
S
160
|
D
D
G
G
T
T
Q
Q
K
K
V
V
T
T
Y
Y
L
L
V
V
170
|
H
H
N
N
F
F
E
E
E
E
G
G
G
G
G
G
V
V
A
A
180
|
M
M
G
G
M
M
Y
Y
N
N
Q
Q
D
D
K
K
S
S
I
I
190
|
E
E
D
D
F
F
A
A
H
H
S
S
S
S
F
F
Q
Q
M
M
200
|
A
A
L
L
S
S
K
K
G
G
W
W
P
P
L
L
Y
Y
L
L
210
|
S
S
T
T
K
K
N
N
T
T
I
I
L
L
K
K
K
K
Y
Y
220
|
D
D
G
G
R
R
F
F
K
K
D
D
I
I
F
F
Q
Q
E
E
230
|
I
I
Y
Y
D
D
K
K
Q
Q
Y
Y
K
K
S
S
Q
Q
F
F
240
|
E
E
A
A
Q
Q
K
K
I
I
W
W
Y
Y
E
E
H
H
R
R
250
|
L
L
I
I
D
D
D
D
M
M
V
V
A
A
Q
Q
A
A
M
M
260
|
K
K
S
S
E
E
G
G
G
G
F
F
I
I
W
W
A
A
C
C
270
|
K
K
N
N
Y
Y
D
D
G
G
D
D
V
V
Q
Q
S
S
D
D
280
|
S
S
V
V
A
A
Q
Q
G
G
Y
Y
G
G
S
S
L
L
G
G
290
|
M
M
M
M
T
T
S
S
V
V
L
L
V
V
C
C
P
P
D
D
300
|
G
G
K
K
T
T
V
V
E
E
A
A
E
E
A
A
A
A
H
H
310
|
G
G
T
T
V
V
T
T
R
R
H
H
Y
Y
R
R
M
M
Y
Y
320
|
Q
Q
K
K
G
G
Q
Q
E
E
T
T
S
S
T
T
N
N
P
P
330
|
I
I
A
A
S
S
I
I
F
F
A
A
W
W
T
T
R
R
G
G
340
|
L
L
A
A
H
H
R
R
A
A
K
K
L
L
D
D
N
N
N
N
350
|
K
K
E
E
L
L
A
A
F
F
F
F
A
A
N
N
A
A
L
L
360
|
E
E
E
E
V
V
S
S
I
I
E
E
T
T
I
I
E
E
A
A
370
|
G
G
F
F
M
M
T
T
K
K
D
D
L
L
A
A
A
A
C
C
380
|
I
I
K
K
G
G
L
L
P
P
N
N
V
V
Q
Q
R
R
S
S
390
|
D
D
Y
Y
L
L
N
N
T
T
F
F
E
E
F
F
M
M
D
D
400
|
K
K
L
L
G
G
E
E
N
N
L
L
K
K
I
I
K
K
L
L
410
|
A
A
Q
Q
A
A
K
K
L
L
S
S
L
L
E
E
H
H
H
H
420
|
H
H
H
H
H
H
H
H
H
H
H
H
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
In Vitro Model IDH2 cells Ovary Homo sapiens (Human) CVCL_D3DY
IDH1 cells Ovary Homo sapiens (Human) CVCL_D3DY
In Vivo Model Female athymic nu/nu mouse PDX model Mus musculus
Experiment for
Drug Resistance		 Promega assay
Mechanism Description The oncometabolite, 2-hydroxyglutarate, renders IDH1/2 mutant cancer cells deficient in homologous recombination and confers vulnerability to synthetic lethal targeting with PARP inhibitors.
Key Molecule: Oxalosuccinate decarboxylase (IDH1) [6]
Sensitive Disease Brain glioma [ICD-11: 2A00.0]
Sensitive Drug Talazoparib
 Drug Info 
Molecule Alteration Missense mutation
p.R132C (c.394C>T)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.93  Å
PDB: 5GIR
Mutant Type Structure Method: X-ray diffraction Resolution: 2.20  Å
PDB: 6IO0
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.64
TM score: 0.30204
Amino acid change:
R132C
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
-
M
-
S
-
K
-
K
-
I
-
S
-
G
-
G
-
S
10
|
-
V
-
V
-
E
-
M
-
Q
-
G
-
D
-
E
-
M
-
T
20
|
-
R
-
I
-
I
-
W
-
E
-
L
-
I
-
K
-
E
-
K
30
|
-
L
-
I
-
F
-
P
-
Y
-
V
-
E
-
L
-
D
-
L
40
|
-
H
-
S
-
Y
-
D
-
L
-
G
-
I
-
E
-
N
-
R
50
|
-
D
-
A
-
T
-
N
-
D
-
Q
-
V
-
T
-
K
-
D
60
|
-
A
-
A
-
E
-
A
-
I
-
K
-
K
-
H
-
N
-
V
70
|
-
G
-
V
-
K
-
C
-
A
-
T
-
I
-
T
-
P
-
D
80
|
-
E
-
K
-
R
-
V
-
E
-
E
-
F
-
K
-
L
-
K
90
|
-
Q
-
M
-
W
-
K
-
S
-
P
-
N
-
G
-
T
-
I
100
|
-
R
-
N
-
I
-
L
-
G
-
G
-
T
-
V
-
F
-
R
110
|
-
E
-
A
-
I
-
I
-
C
-
K
-
N
-
I
-
P
-
R
120
|
-
L
-
V
-
S
-
G
-
W
-
V
K
K
P
P
I
I
I
I
130
|
I
I
G
G
S
C
H
H
A
A
Y
Y
G
G
D
D
-
Q
-
Y
140
|
-
R
-
A
-
T
-
D
-
F
-
V
-
V
-
P
-
G
-
P
150
|
-
G
-
K
-
V
-
E
-
I
-
T
-
Y
-
T
-
P
-
S
160
|
-
D
-
G
-
T
-
Q
-
K
-
V
-
T
-
Y
-
L
-
V
170
|
-
H
-
N
-
F
-
E
-
E
-
G
-
G
-
G
-
V
-
A
180
|
-
M
-
G
-
M
-
Y
-
N
-
Q
-
D
-
K
-
S
-
I
190
|
-
E
-
D
-
F
-
A
-
H
-
S
-
S
-
F
-
Q
-
M
200
|
-
A
-
L
-
S
-
K
-
G
-
W
-
P
-
L
-
Y
-
L
210
|
-
S
-
T
-
K
-
N
-
T
-
I
-
L
-
K
-
K
-
Y
220
|
-
D
-
G
-
R
-
F
-
K
-
D
-
I
-
F
-
Q
-
E
230
|
-
I
-
Y
-
D
-
K
-
Q
-
Y
-
K
-
S
-
Q
-
F
240
|
-
E
-
A
-
Q
-
K
-
I
-
W
-
Y
-
E
-
H
-
R
250
|
-
L
-
I
-
D
-
D
-
M
-
V
-
A
-
Q
-
A
-
M
260
|
-
K
-
S
-
E
-
G
-
G
-
F
-
I
-
W
-
A
-
C
270
|
-
K
-
N
-
Y
-
D
-
G
-
D
-
V
-
Q
-
S
-
D
280
|
-
S
-
V
-
A
-
Q
-
G
-
Y
-
G
-
S
-
L
-
G
290
|
-
M
-
M
-
T
-
S
-
V
-
L
-
V
-
C
-
P
-
D
300
|
-
G
-
K
-
T
-
V
-
E
-
A
-
E
-
A
-
A
-
H
310
|
-
G
-
T
-
V
-
T
-
R
-
H
-
Y
-
R
-
M
-
Y
320
|
-
Q
-
K
-
G
-
Q
-
E
-
T
-
S
-
T
-
N
-
P
330
|
-
I
-
A
-
S
-
I
-
F
-
A
-
W
-
T
-
R
-
G
340
|
-
L
-
A
-
H
-
R
-
A
-
K
-
L
-
D
-
N
-
N
350
|
-
K
-
E
-
L
-
A
-
F
-
F
-
A
-
N
-
A
-
L
360
|
-
E
-
E
-
V
-
S
-
I
-
E
-
T
-
I
-
E
-
A
370
|
-
G
-
F
-
M
-
T
-
K
-
D
-
L
-
A
-
A
-
C
380
|
-
I
-
K
-
G
-
L
-
P
-
N
-
V
-
Q
-
R
-
S
390
|
-
D
-
Y
-
L
-
N
-
T
-
F
-
E
-
F
-
M
-
D
400
|
-
K
-
L
-
G
-
E
-
N
-
L
-
K
-
I
-
K
-
L
410
|
-
A
-
Q
-
A
-
K
-
L
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
In Vitro Model IDH2 cells Ovary Homo sapiens (Human) CVCL_D3DY
IDH1 cells Ovary Homo sapiens (Human) CVCL_D3DY
In Vivo Model Female athymic nu/nu mouse PDX model Mus musculus
Experiment for
Drug Resistance		 Promega assay
Mechanism Description The oncometabolite, 2-hydroxyglutarate, renders IDH1/2 mutant cancer cells deficient in homologous recombination and confers vulnerability to synthetic lethal targeting with PARP inhibitors.
Clinical Trial Drug(s)
5 drug(s) in total
Click to Show/Hide the Full List of Drugs
Capivasertib
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Key Molecule: RAC-alpha serine/threonine-protein kinase (AKT1) [7]
Sensitive Disease Brain glioma [ICD-11: 2A00.0]
Sensitive Drug Capivasertib
 Drug Info 
Molecule Alteration Missense mutation
p.E17K (c.49G>A)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.65  Å
PDB: 1UNP
Mutant Type Structure Method: X-ray diffraction Resolution: 1.94  Å
PDB: 2UZR
   Download The Information of Sequence       Download The Structure File   
RMSD: 0.26
TM score: 0.99569
Amino acid change:
E17K
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
0
|
-
S
M
M
S
S
D
D
V
V
A
A
I
I
V
V
K
K
E
E
10
|
G
G
W
W
L
L
H
H
K
K
R
R
G
G
E
K
Y
Y
I
I
20
|
K
K
T
T
W
W
R
R
P
P
R
R
Y
Y
F
F
L
L
L
L
30
|
K
K
N
N
D
D
G
G
T
T
F
F
I
I
G
G
Y
Y
K
K
40
|
E
E
R
R
P
P
Q
Q
D
D
V
V
D
D
Q
Q
R
R
E
E
50
|
A
A
P
P
L
L
N
N
N
N
F
F
S
S
V
V
A
A
Q
Q
60
|
C
C
Q
Q
L
L
M
M
K
K
T
T
E
E
R
R
P
P
R
R
70
|
P
P
N
N
T
T
F
F
I
I
I
I
R
R
C
C
L
L
Q
Q
80
|
W
W
T
T
T
T
V
V
I
I
E
E
R
R
T
T
F
F
H
H
90
|
V
V
E
E
T
T
P
P
E
E
E
E
R
R
E
E
E
E
W
W
100
|
T
T
T
T
A
A
I
I
Q
Q
T
T
V
V
A
A
D
D
G
G
110
|
L
L
K
K
K
K
Q
Q
E
E
E
E
E
E
E
E
M
M
D
D
120
|
F
F
R
R
-
S
-
G
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
In Vitro Model Brain N.A.
Mechanism Description The missense mutation p.E17K (c.49G>A) in gene AKT1 cause the sensitivity of Capivasertib by aberration of the drug's therapeutic target
Enasidenib
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
Key Molecule: Isocitrate dehydrogenase NADP 2 (IDH2) [8]
Sensitive Disease FGFR-tacc positive glioblastoma [ICD-11: 2A00.01]
Sensitive Drug Enasidenib
 Drug Info 
Molecule Alteration Missense mutation
p.R172K (c.515G>A)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.93  Å
PDB: 5GIS
Mutant Type Structure Method: X-ray diffraction Resolution: 2.10  Å
PDB: 5SVN
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.13
TM score: 0.29352
Amino acid change:
R172K
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
40
|
-
A
-
D
-
K
-
R
-
I
-
K
-
V
-
A
-
K
-
P
50
|
-
V
-
V
-
E
-
M
-
D
-
G
-
D
-
E
-
M
-
T
60
|
-
R
-
I
-
I
-
W
-
Q
-
F
-
I
-
K
-
E
-
K
70
|
-
L
-
I
-
L
-
P
-
H
-
V
-
D
-
I
-
Q
-
L
80
|
-
K
-
Y
-
F
-
D
-
L
-
G
-
L
-
P
-
N
-
R
90
|
-
D
-
Q
-
T
-
D
-
D
-
Q
-
V
-
T
-
I
-
D
100
|
-
S
-
A
-
L
-
A
-
T
-
Q
-
K
-
Y
-
S
-
V
110
|
-
A
-
V
-
K
-
C
-
A
-
T
-
I
-
T
-
P
-
D
120
|
-
E
-
A
-
R
-
V
-
E
-
E
-
F
-
K
-
L
-
K
130
|
-
K
-
M
-
W
-
K
-
S
-
P
-
N
-
G
-
T
-
I
140
|
-
R
-
N
-
I
-
L
-
G
-
G
-
T
-
V
-
F
-
R
150
|
-
E
-
P
-
I
-
I
-
C
-
K
-
N
-
I
-
P
-
R
160
|
-
L
-
V
-
P
-
G
-
W
T
T
K
K
P
P
I
I
T
T
170
|
I
I
G
G
S
K
H
H
A
A
H
H
G
G
D
D
Q
Q
Y
Y
180
|
K
K
-
A
-
T
-
D
-
F
-
V
-
A
-
D
-
R
-
A
190
|
-
G
-
T
-
F
-
K
-
M
-
V
-
F
-
T
-
P
-
K
200
|
-
D
-
G
-
S
-
G
-
V
-
K
-
E
-
W
-
E
-
V
210
|
-
Y
-
N
-
F
-
P
-
A
-
G
-
G
-
V
-
G
-
M
220
|
-
G
-
M
-
Y
-
N
-
T
-
D
-
E
-
S
-
I
-
S
230
|
-
G
-
F
-
A
-
H
-
S
-
C
-
F
-
Q
-
Y
-
A
240
|
-
I
-
Q
-
K
-
K
-
W
-
P
-
L
-
Y
-
M
-
S
250
|
-
T
-
K
-
N
-
T
-
I
-
L
-
K
-
A
-
Y
-
D
260
|
-
G
-
R
-
F
-
K
-
D
-
I
-
F
-
Q
-
E
-
I
270
|
-
F
-
D
-
K
-
H
-
Y
-
K
-
T
-
D
-
F
-
D
280
|
-
K
-
N
-
K
-
I
-
W
-
Y
-
E
-
H
-
R
-
L
290
|
-
I
-
D
-
D
-
M
-
V
-
A
-
Q
-
V
-
L
-
K
300
|
-
S
-
S
-
G
-
G
-
F
-
V
-
W
-
A
-
C
-
K
310
|
-
N
-
Y
-
D
-
G
-
D
-
V
-
Q
-
S
-
D
-
I
320
|
-
L
-
A
-
Q
-
G
-
F
-
G
-
S
-
L
-
G
-
L
330
|
-
M
-
T
-
S
-
V
-
L
-
V
-
C
-
P
-
D
-
G
340
|
-
K
-
T
-
I
-
E
-
A
-
E
-
A
-
A
-
H
-
G
350
|
-
T
-
V
-
T
-
R
-
H
-
Y
-
R
-
E
-
H
-
Q
360
|
-
K
-
G
-
R
-
P
-
T
-
S
-
T
-
N
-
P
-
I
370
|
-
A
-
S
-
I
-
F
-
A
-
W
-
T
-
R
-
G
-
L
380
|
-
E
-
H
-
R
-
G
-
K
-
L
-
D
-
G
-
N
-
Q
390
|
-
D
-
L
-
I
-
R
-
F
-
A
-
Q
-
M
-
L
-
E
400
|
-
K
-
V
-
C
-
V
-
E
-
T
-
V
-
E
-
S
-
G
410
|
-
A
-
M
-
T
-
K
-
D
-
L
-
A
-
G
-
C
-
I
420
|
-
H
-
G
-
L
-
S
-
N
-
V
-
K
-
L
-
N
-
E
430
|
-
H
-
F
-
L
-
N
-
T
-
T
-
D
-
F
-
L
-
D
440
|
-
T
-
I
-
K
-
S
-
N
-
L
-
D
-
R
-
A
-
L
450
|
-
G
-
R
-
Q
-
S
-
L
-
E
-
H
-
H
-
H
-
H
460
|
-
H
-
H
-
H
-
H
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
In Vitro Model U87MG cells Brain Homo sapiens (Human) CVCL_GP63
TF-1 cells Bone marrow Homo sapiens (Human) CVCL_0559
TF-1a cells Bone marrow Homo sapiens (Human) CVCL_3608
IDH2 cells Ovary Homo sapiens (Human) CVCL_D3DY
In Vivo Model NSG mouse PDX model Mus musculus
Mechanism Description Somatic gain-of-function mutations in isocitrate dehydrogenases (IDH) 1 and 2 are found in multiple hematologic and solid tumors, leading to accumulation of the oncometabolite (R)-2-hydroxyglutarate (2HG). 2HG competitively inhibits alpha-ketoglutarate-dependent dioxygenases, including histone demethylases and methylcytosine dioxygenases of the TET family, causing epigenetic dysregulation and a block in cellular differentiation.
Key Molecule: Isocitrate dehydrogenase NADP 2 (IDH2) [8]
Sensitive Disease FGFR-tacc positive glioblastoma [ICD-11: 2A00.01]
Sensitive Drug Enasidenib
 Drug Info 
Molecule Alteration Missense mutation
p.R140Q (c.419G>A)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 2.10  Å
PDB: 5SVN
Mutant Type Structure Method: X-ray diffraction Resolution: 1.54  Å
PDB: 5I95
   Download The Information of Sequence       Download The Structure File   
RMSD: 0.33
TM score: 0.99798
Amino acid change:
R140Q
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
-
M
40
|
A
A
D
D
K
K
R
R
I
I
K
K
V
V
A
A
K
K
P
P
50
|
V
V
V
V
E
E
M
M
D
D
G
G
D
D
E
E
M
M
T
T
60
|
R
R
I
I
I
I
W
W
Q
Q
F
F
I
I
K
K
E
E
K
K
70
|
L
L
I
I
L
L
P
P
H
H
V
V
D
D
I
I
Q
Q
L
L
80
|
K
K
Y
Y
F
F
D
D
L
L
G
G
L
L
P
P
N
N
R
R
90
|
D
D
Q
Q
T
T
D
D
D
D
Q
Q
V
V
T
T
I
I
D
D
100
|
S
S
A
A
L
L
A
A
T
T
Q
Q
K
K
Y
Y
S
S
V
V
110
|
A
A
V
V
K
K
C
C
A
A
T
T
I
I
T
T
P
P
D
D
120
|
E
E
A
A
R
R
V
V
E
E
E
E
F
F
K
K
L
L
K
K
130
|
K
K
M
M
W
W
K
K
S
S
P
P
N
N
G
G
T
T
I
I
140
|
R
Q
N
N
I
I
L
L
G
G
G
G
T
T
V
V
F
F
R
R
150
|
E
E
P
P
I
I
I
I
C
C
K
K
N
N
I
I
P
P
R
R
160
|
L
L
V
V
P
P
G
G
W
W
T
T
K
K
P
P
I
I
T
T
170
|
I
I
G
G
K
R
H
H
A
A
H
H
G
G
D
D
Q
Q
Y
Y
180
|
K
K
A
A
T
T
D
D
F
F
V
V
A
A
D
D
R
R
A
A
190
|
G
G
T
T
F
F
K
K
M
M
V
V
F
F
T
T
P
P
K
K
200
|
D
D
G
G
S
S
G
G
V
V
K
K
E
E
W
W
E
E
V
V
210
|
Y
Y
N
N
F
F
P
P
A
A
G
G
G
G
V
V
G
G
M
M
220
|
G
G
M
M
Y
Y
N
N
T
T
D
D
E
E
S
S
I
I
S
S
230
|
G
G
F
F
A
A
H
H
S
S
C
C
F
F
Q
Q
Y
Y
A
A
240
|
I
I
Q
Q
K
K
K
K
W
W
P
P
L
L
Y
Y
M
M
S
S
250
|
T
T
K
K
N
N
T
T
I
I
L
L
K
K
A
A
Y
Y
D
D
260
|
G
G
R
R
F
F
K
K
D
D
I
I
F
F
Q
Q
E
E
I
I
270
|
F
F
D
D
K
K
H
H
Y
Y
K
K
T
T
D
D
F
F
D
D
280
|
K
K
N
N
K
K
I
I
W
W
Y
Y
E
E
H
H
R
R
L
L
290
|
I
I
D
D
D
D
M
M
V
V
A
A
Q
Q
V
V
L
L
K
K
300
|
S
S
S
S
G
G
G
G
F
F
V
V
W
W
A
A
C
C
K
K
310
|
N
N
Y
Y
D
D
G
G
D
D
V
V
Q
Q
S
S
D
D
I
I
320
|
L
L
A
A
Q
Q
G
G
F
F
G
G
S
S
L
L
G
G
L
L
330
|
M
M
T
T
S
S
V
V
L
L
V
V
C
C
P
P
D
D
G
G
340
|
K
K
T
T
I
I
E
E
A
A
E
E
A
A
A
A
H
H
G
G
350
|
T
T
V
V
T
T
R
R
H
H
Y
Y
R
R
E
E
H
H
Q
Q
360
|
K
K
G
G
R
R
P
P
T
T
S
S
T
T
N
N
P
P
I
I
370
|
A
A
S
S
I
I
F
F
A
A
W
W
T
T
R
R
G
G
L
L
380
|
E
E
H
H
R
R
G
G
K
K
L
L
D
D
G
G
N
N
Q
Q
390
|
D
D
L
L
I
I
R
R
F
F
A
A
Q
Q
M
M
L
L
E
E
400
|
K
K
V
V
C
C
V
V
E
E
T
T
V
V
E
E
S
S
G
G
410
|
A
A
M
M
T
T
K
K
D
D
L
L
A
A
G
G
C
C
I
I
420
|
H
H
G
G
L
L
S
S
N
N
V
V
K
K
L
L
N
N
E
E
430
|
H
H
F
F
L
L
N
N
T
T
T
T
D
D
F
F
L
L
D
D
440
|
T
T
I
I
K
K
S
S
N
N
L
L
D
D
R
R
A
A
L
L
450
|
G
G
R
R
Q
Q
S
L
L
E
E
H
H
H
H
H
H
H
H
H
460
|
H
H
H
H
H
H
H
-
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
In Vitro Model U87MG cells Brain Homo sapiens (Human) CVCL_GP63
TF-1 cells Bone marrow Homo sapiens (Human) CVCL_0559
TF-1a cells Bone marrow Homo sapiens (Human) CVCL_3608
IDH2 cells Ovary Homo sapiens (Human) CVCL_D3DY
In Vivo Model NSG mouse PDX model Mus musculus
Mechanism Description Somatic gain-of-function mutations in isocitrate dehydrogenases (IDH) 1 and 2 are found in multiple hematologic and solid tumors, leading to accumulation of the oncometabolite (R)-2-hydroxyglutarate (2HG). 2HG competitively inhibits alpha-ketoglutarate-dependent dioxygenases, including histone demethylases and methylcytosine dioxygenases of the TET family, causing epigenetic dysregulation and a block in cellular differentiation.
Selumetinib
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [9]
Sensitive Disease FGFR-tacc positive glioblastoma [ICD-11: 2A00.01]
Sensitive Drug Selumetinib
 Drug Info 
Molecule Alteration Missense mutation
p.V600E (c.1799T>A)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 2.55  Å
PDB: 4E26
Mutant Type Structure Method: X-ray diffraction Resolution: 3.20  Å
PDB: 4G9R
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.53
TM score: 0.95765
Amino acid change:
V600E
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
420
|
M
M
D
D
R
R
G
G
S
S
H
H
H
H
H
H
H
H
H
H
430
|
H
H
G
G
S
S
E
E
D
D
R
R
N
N
R
R
M
M
K
K
440
|
T
T
L
L
G
G
R
R
R
R
D
D
S
S
S
S
D
D
D
D
450
|
W
W
E
E
I
I
P
P
D
D
G
G
Q
Q
I
I
T
T
V
V
460
|
G
G
Q
Q
R
R
I
I
G
G
S
S
G
G
S
S
F
F
G
G
470
|
T
T
V
V
Y
Y
K
K
G
G
K
K
W
W
H
H
G
G
D
D
480
|
V
V
A
A
V
V
K
K
M
M
L
L
N
N
V
V
T
T
A
A
490
|
P
P
T
T
P
P
Q
Q
Q
Q
L
L
Q
Q
A
A
F
F
K
K
500
|
N
N
E
E
V
V
G
G
V
V
L
L
R
R
K
K
T
T
R
R
510
|
H
H
V
V
N
N
I
I
L
L
L
L
F
F
M
M
G
G
Y
Y
520
|
S
S
T
T
K
K
P
P
Q
Q
L
L
A
A
I
I
V
V
T
T
530
|
Q
Q
W
W
C
C
E
E
G
G
S
S
S
S
L
L
Y
Y
H
H
540
|
H
H
L
L
H
H
I
I
I
I
E
E
T
T
K
K
F
F
E
E
550
|
M
M
I
I
K
K
L
L
I
I
D
D
I
I
A
A
R
R
Q
Q
560
|
T
T
A
A
Q
Q
G
G
M
M
D
D
Y
Y
L
L
H
H
A
A
570
|
K
K
S
S
I
I
I
I
H
H
R
R
D
D
L
L
K
K
S
S
580
|
N
N
N
N
I
I
F
F
L
L
H
H
E
E
D
D
L
L
T
T
590
|
V
V
K
K
I
I
G
G
D
D
F
F
G
G
L
L
A
A
T
T
600
|
V
E
K
K
S
S
R
R
W
W
S
S
G
G
S
S
H
H
Q
Q
610
|
F
F
E
E
Q
Q
L
L
S
S
G
G
S
S
I
I
L
L
W
W
620
|
M
M
A
A
P
P
E
E
V
V
I
I
R
R
M
M
Q
Q
D
D
630
|
K
K
N
N
P
P
Y
Y
S
S
F
F
Q
Q
S
S
D
D
V
V
640
|
Y
Y
A
A
F
F
G
G
I
I
V
V
L
L
Y
Y
E
E
L
L
650
|
M
M
T
T
G
G
Q
Q
L
L
P
P
Y
Y
S
S
N
N
I
I
660
|
N
N
N
N
R
R
D
D
Q
Q
I
I
I
I
F
F
M
M
V
V
670
|
G
G
R
R
G
G
Y
Y
L
L
S
S
P
P
D
D
L
L
S
S
680
|
K
K
V
V
R
R
S
S
N
N
C
C
P
P
K
K
A
A
M
M
690
|
K
K
R
R
L
L
M
M
A
A
E
E
C
C
L
L
K
K
K
K
700
|
K
K
R
R
D
D
E
E
R
R
P
P
L
L
F
F
P
P
Q
Q
710
|
I
I
L
L
A
A
S
S
I
I
E
E
L
L
L
L
A
A
R
R
720
|
S
S
L
L
P
P
K
K
I
I
H
H
R
R
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [9]
Sensitive Disease FGFR-tacc positive glioblastoma [ICD-11: 2A00.01]
Sensitive Drug Selumetinib
 Drug Info 
Molecule Alteration Missense mutation
p.V600E (c.1799T>A)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 2.55  Å
PDB: 4E26
Mutant Type Structure Method: X-ray diffraction Resolution: 3.20  Å
PDB: 4G9R
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.53
TM score: 0.95765
Amino acid change:
V600E
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
420
|
M
M
D
D
R
R
G
G
S
S
H
H
H
H
H
H
H
H
H
H
430
|
H
H
G
G
S
S
E
E
D
D
R
R
N
N
R
R
M
M
K
K
440
|
T
T
L
L
G
G
R
R
R
R
D
D
S
S
S
S
D
D
D
D
450
|
W
W
E
E
I
I
P
P
D
D
G
G
Q
Q
I
I
T
T
V
V
460
|
G
G
Q
Q
R
R
I
I
G
G
S
S
G
G
S
S
F
F
G
G
470
|
T
T
V
V
Y
Y
K
K
G
G
K
K
W
W
H
H
G
G
D
D
480
|
V
V
A
A
V
V
K
K
M
M
L
L
N
N
V
V
T
T
A
A
490
|
P
P
T
T
P
P
Q
Q
Q
Q
L
L
Q
Q
A
A
F
F
K
K
500
|
N
N
E
E
V
V
G
G
V
V
L
L
R
R
K
K
T
T
R
R
510
|
H
H
V
V
N
N
I
I
L
L
L
L
F
F
M
M
G
G
Y
Y
520
|
S
S
T
T
K
K
P
P
Q
Q
L
L
A
A
I
I
V
V
T
T
530
|
Q
Q
W
W
C
C
E
E
G
G
S
S
S
S
L
L
Y
Y
H
H
540
|
H
H
L
L
H
H
I
I
I
I
E
E
T
T
K
K
F
F
E
E
550
|
M
M
I
I
K
K
L
L
I
I
D
D
I
I
A
A
R
R
Q
Q
560
|
T
T
A
A
Q
Q
G
G
M
M
D
D
Y
Y
L
L
H
H
A
A
570
|
K
K
S
S
I
I
I
I
H
H
R
R
D
D
L
L
K
K
S
S
580
|
N
N
N
N
I
I
F
F
L
L
H
H
E
E
D
D
L
L
T
T
590
|
V
V
K
K
I
I
G
G
D
D
F
F
G
G
L
L
A
A
T
T
600
|
V
E
K
K
S
S
R
R
W
W
S
S
G
G
S
S
H
H
Q
Q
610
|
F
F
E
E
Q
Q
L
L
S
S
G
G
S
S
I
I
L
L
W
W
620
|
M
M
A
A
P
P
E
E
V
V
I
I
R
R
M
M
Q
Q
D
D
630
|
K
K
N
N
P
P
Y
Y
S
S
F
F
Q
Q
S
S
D
D
V
V
640
|
Y
Y
A
A
F
F
G
G
I
I
V
V
L
L
Y
Y
E
E
L
L
650
|
M
M
T
T
G
G
Q
Q
L
L
P
P
Y
Y
S
S
N
N
I
I
660
|
N
N
N
N
R
R
D
D
Q
Q
I
I
I
I
F
F
M
M
V
V
670
|
G
G
R
R
G
G
Y
Y
L
L
S
S
P
P
D
D
L
L
S
S
680
|
K
K
V
V
R
R
S
S
N
N
C
C
P
P
K
K
A
A
M
M
690
|
K
K
R
R
L
L
M
M
A
A
E
E
C
C
L
L
K
K
K
K
700
|
K
K
R
R
D
D
E
E
R
R
P
P
L
L
F
F
P
P
Q
Q
710
|
I
I
L
L
A
A
S
S
I
I
E
E
L
L
L
L
A
A
R
R
720
|
S
S
L
L
P
P
K
K
I
I
H
H
R
R
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
Ulixertinib
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [10]
Sensitive Disease FGFR-tacc positive glioblastoma [ICD-11: 2A00.01]
Sensitive Drug Ulixertinib
 Drug Info 
Molecule Alteration Missense mutation
p.V600E (c.1799T>A)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 2.55  Å
PDB: 4E26
Mutant Type Structure Method: X-ray diffraction Resolution: 3.20  Å
PDB: 4G9R
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.53
TM score: 0.95765
Amino acid change:
V600E
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
420
|
M
M
D
D
R
R
G
G
S
S
H
H
H
H
H
H
H
H
H
H
430
|
H
H
G
G
S
S
E
E
D
D
R
R
N
N
R
R
M
M
K
K
440
|
T
T
L
L
G
G
R
R
R
R
D
D
S
S
S
S
D
D
D
D
450
|
W
W
E
E
I
I
P
P
D
D
G
G
Q
Q
I
I
T
T
V
V
460
|
G
G
Q
Q
R
R
I
I
G
G
S
S
G
G
S
S
F
F
G
G
470
|
T
T
V
V
Y
Y
K
K
G
G
K
K
W
W
H
H
G
G
D
D
480
|
V
V
A
A
V
V
K
K
M
M
L
L
N
N
V
V
T
T
A
A
490
|
P
P
T
T
P
P
Q
Q
Q
Q
L
L
Q
Q
A
A
F
F
K
K
500
|
N
N
E
E
V
V
G
G
V
V
L
L
R
R
K
K
T
T
R
R
510
|
H
H
V
V
N
N
I
I
L
L
L
L
F
F
M
M
G
G
Y
Y
520
|
S
S
T
T
K
K
P
P
Q
Q
L
L
A
A
I
I
V
V
T
T
530
|
Q
Q
W
W
C
C
E
E
G
G
S
S
S
S
L
L
Y
Y
H
H
540
|
H
H
L
L
H
H
I
I
I
I
E
E
T
T
K
K
F
F
E
E
550
|
M
M
I
I
K
K
L
L
I
I
D
D
I
I
A
A
R
R
Q
Q
560
|
T
T
A
A
Q
Q
G
G
M
M
D
D
Y
Y
L
L
H
H
A
A
570
|
K
K
S
S
I
I
I
I
H
H
R
R
D
D
L
L
K
K
S
S
580
|
N
N
N
N
I
I
F
F
L
L
H
H
E
E
D
D
L
L
T
T
590
|
V
V
K
K
I
I
G
G
D
D
F
F
G
G
L
L
A
A
T
T
600
|
V
E
K
K
S
S
R
R
W
W
S
S
G
G
S
S
H
H
Q
Q
610
|
F
F
E
E
Q
Q
L
L
S
S
G
G
S
S
I
I
L
L
W
W
620
|
M
M
A
A
P
P
E
E
V
V
I
I
R
R
M
M
Q
Q
D
D
630
|
K
K
N
N
P
P
Y
Y
S
S
F
F
Q
Q
S
S
D
D
V
V
640
|
Y
Y
A
A
F
F
G
G
I
I
V
V
L
L
Y
Y
E
E
L
L
650
|
M
M
T
T
G
G
Q
Q
L
L
P
P
Y
Y
S
S
N
N
I
I
660
|
N
N
N
N
R
R
D
D
Q
Q
I
I
I
I
F
F
M
M
V
V
670
|
G
G
R
R
G
G
Y
Y
L
L
S
S
P
P
D
D
L
L
S
S
680
|
K
K
V
V
R
R
S
S
N
N
C
C
P
P
K
K
A
A
M
M
690
|
K
K
R
R
L
L
M
M
A
A
E
E
C
C
L
L
K
K
K
K
700
|
K
K
R
R
D
D
E
E
R
R
P
P
L
L
F
F
P
P
Q
Q
710
|
I
I
L
L
A
A
S
S
I
I
E
E
L
L
L
L
A
A
R
R
720
|
S
S
L
L
P
P
K
K
I
I
H
H
R
R
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation MAPK signaling pathway Inhibition hsa04010
PLX4720
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [11]
Resistant Disease FGFR-tacc positive glioblastoma [ICD-11: 2A00.01]
Resistant Drug PLX4720
 Drug Info 
Molecule Alteration Missense mutation
p.V600E (c.1799T>A)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 2.55  Å
PDB: 4E26
Mutant Type Structure Method: X-ray diffraction Resolution: 3.20  Å
PDB: 4G9R
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.53
TM score: 0.95765
Amino acid change:
V600E
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
420
|
M
M
D
D
R
R
G
G
S
S
H
H
H
H
H
H
H
H
H
H
430
|
H
H
G
G
S
S
E
E
D
D
R
R
N
N
R
R
M
M
K
K
440
|
T
T
L
L
G
G
R
R
R
R
D
D
S
S
S
S
D
D
D
D
450
|
W
W
E
E
I
I
P
P
D
D
G
G
Q
Q
I
I
T
T
V
V
460
|
G
G
Q
Q
R
R
I
I
G
G
S
S
G
G
S
S
F
F
G
G
470
|
T
T
V
V
Y
Y
K
K
G
G
K
K
W
W
H
H
G
G
D
D
480
|
V
V
A
A
V
V
K
K
M
M
L
L
N
N
V
V
T
T
A
A
490
|
P
P
T
T
P
P
Q
Q
Q
Q
L
L
Q
Q
A
A
F
F
K
K
500
|
N
N
E
E
V
V
G
G
V
V
L
L
R
R
K
K
T
T
R
R
510
|
H
H
V
V
N
N
I
I
L
L
L
L
F
F
M
M
G
G
Y
Y
520
|
S
S
T
T
K
K
P
P
Q
Q
L
L
A
A
I
I
V
V
T
T
530
|
Q
Q
W
W
C
C
E
E
G
G
S
S
S
S
L
L
Y
Y
H
H
540
|
H
H
L
L
H
H
I
I
I
I
E
E
T
T
K
K
F
F
E
E
550
|
M
M
I
I
K
K
L
L
I
I
D
D
I
I
A
A
R
R
Q
Q
560
|
T
T
A
A
Q
Q
G
G
M
M
D
D
Y
Y
L
L
H
H
A
A
570
|
K
K
S
S
I
I
I
I
H
H
R
R
D
D
L
L
K
K
S
S
580
|
N
N
N
N
I
I
F
F
L
L
H
H
E
E
D
D
L
L
T
T
590
|
V
V
K
K
I
I
G
G
D
D
F
F
G
G
L
L
A
A
T
T
600
|
V
E
K
K
S
S
R
R
W
W
S
S
G
G
S
S
H
H
Q
Q
610
|
F
F
E
E
Q
Q
L
L
S
S
G
G
S
S
I
I
L
L
W
W
620
|
M
M
A
A
P
P
E
E
V
V
I
I
R
R
M
M
Q
Q
D
D
630
|
K
K
N
N
P
P
Y
Y
S
S
F
F
Q
Q
S
S
D
D
V
V
640
|
Y
Y
A
A
F
F
G
G
I
I
V
V
L
L
Y
Y
E
E
L
L
650
|
M
M
T
T
G
G
Q
Q
L
L
P
P
Y
Y
S
S
N
N
I
I
660
|
N
N
N
N
R
R
D
D
Q
Q
I
I
I
I
F
F
M
M
V
V
670
|
G
G
R
R
G
G
Y
Y
L
L
S
S
P
P
D
D
L
L
S
S
680
|
K
K
V
V
R
R
S
S
N
N
C
C
P
P
K
K
A
A
M
M
690
|
K
K
R
R
L
L
M
M
A
A
E
E
C
C
L
L
K
K
K
K
700
|
K
K
R
R
D
D
E
E
R
R
P
P
L
L
F
F
P
P
Q
Q
710
|
I
I
L
L
A
A
S
S
I
I
E
E
L
L
L
L
A
A
R
R
720
|
S
S
L
L
P
P
K
K
I
I
H
H
R
R
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
In Vitro Model GBM cells Brain Homo sapiens (Human) N.A.
In Vivo Model Athymic mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 qPCR
Experiment for
Drug Resistance		 Alamar blue proliferation assay
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [12]
Sensitive Disease FGFR-tacc positive glioblastoma [ICD-11: 2A00.01]
Sensitive Drug PLX4720
 Drug Info 
Molecule Alteration Missense mutation
p.V600E (c.1799T>A)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 2.55  Å
PDB: 4E26
Mutant Type Structure Method: X-ray diffraction Resolution: 3.20  Å
PDB: 4G9R
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.53
TM score: 0.95765
Amino acid change:
V600E
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
420
|
M
M
D
D
R
R
G
G
S
S
H
H
H
H
H
H
H
H
H
H
430
|
H
H
G
G
S
S
E
E
D
D
R
R
N
N
R
R
M
M
K
K
440
|
T
T
L
L
G
G
R
R
R
R
D
D
S
S
S
S
D
D
D
D
450
|
W
W
E
E
I
I
P
P
D
D
G
G
Q
Q
I
I
T
T
V
V
460
|
G
G
Q
Q
R
R
I
I
G
G
S
S
G
G
S
S
F
F
G
G
470
|
T
T
V
V
Y
Y
K
K
G
G
K
K
W
W
H
H
G
G
D
D
480
|
V
V
A
A
V
V
K
K
M
M
L
L
N
N
V
V
T
T
A
A
490
|
P
P
T
T
P
P
Q
Q
Q
Q
L
L
Q
Q
A
A
F
F
K
K
500
|
N
N
E
E
V
V
G
G
V
V
L
L
R
R
K
K
T
T
R
R
510
|
H
H
V
V
N
N
I
I
L
L
L
L
F
F
M
M
G
G
Y
Y
520
|
S
S
T
T
K
K
P
P
Q
Q
L
L
A
A
I
I
V
V
T
T
530
|
Q
Q
W
W
C
C
E
E
G
G
S
S
S
S
L
L
Y
Y
H
H
540
|
H
H
L
L
H
H
I
I
I
I
E
E
T
T
K
K
F
F
E
E
550
|
M
M
I
I
K
K
L
L
I
I
D
D
I
I
A
A
R
R
Q
Q
560
|
T
T
A
A
Q
Q
G
G
M
M
D
D
Y
Y
L
L
H
H
A
A
570
|
K
K
S
S
I
I
I
I
H
H
R
R
D
D
L
L
K
K
S
S
580
|
N
N
N
N
I
I
F
F
L
L
H
H
E
E
D
D
L
L
T
T
590
|
V
V
K
K
I
I
G
G
D
D
F
F
G
G
L
L
A
A
T
T
600
|
V
E
K
K
S
S
R
R
W
W
S
S
G
G
S
S
H
H
Q
Q
610
|
F
F
E
E
Q
Q
L
L
S
S
G
G
S
S
I
I
L
L
W
W
620
|
M
M
A
A
P
P
E
E
V
V
I
I
R
R
M
M
Q
Q
D
D
630
|
K
K
N
N
P
P
Y
Y
S
S
F
F
Q
Q
S
S
D
D
V
V
640
|
Y
Y
A
A
F
F
G
G
I
I
V
V
L
L
Y
Y
E
E
L
L
650
|
M
M
T
T
G
G
Q
Q
L
L
P
P
Y
Y
S
S
N
N
I
I
660
|
N
N
N
N
R
R
D
D
Q
Q
I
I
I
I
F
F
M
M
V
V
670
|
G
G
R
R
G
G
Y
Y
L
L
S
S
P
P
D
D
L
L
S
S
680
|
K
K
V
V
R
R
S
S
N
N
C
C
P
P
K
K
A
A
M
M
690
|
K
K
R
R
L
L
M
M
A
A
E
E
C
C
L
L
K
K
K
K
700
|
K
K
R
R
D
D
E
E
R
R
P
P
L
L
F
F
P
P
Q
Q
710
|
I
I
L
L
A
A
S
S
I
I
E
E
L
L
L
L
A
A
R
R
720
|
S
S
L
L
P
P
K
K
I
I
H
H
R
R
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
In Vitro Model LN229 cells Brain Homo sapiens (Human) CVCL_0393
A172 cells Brain Homo sapiens (Human) CVCL_0131
U87 cells Brain Homo sapiens (Human) CVCL_0022
SNB19 cells Brain Homo sapiens (Human) CVCL_0535
U138 cells Brain Homo sapiens (Human) CVCL_0020
T98G cells Brain Homo sapiens (Human) CVCL_0556
HS683 cells Brain Homo sapiens (Human) CVCL_0844
DBTRG-05MG cells Brain Homo sapiens (Human) CVCL_1169
NMC-G1 cells Brain Homo sapiens (Human) CVCL_1608
MO59J cells Brain Homo sapiens (Human) CVCL_0400
LN405 cells Brain Homo sapiens (Human) CVCL_1378
LN172 cells N.A. N.A. N.A.
KG1c cells Brain Homo sapiens (Human) CVCL_2971
H4 cells Brain Homo sapiens (Human) CVCL_1239
GMS10 cells Brain Homo sapiens (Human) CVCL_1233
GAMG cells Brain Homo sapiens (Human) CVCL_1226
CCF-STTG1 cells Brain Homo sapiens (Human) CVCL_1118
AM-38 cells Brain Homo sapiens (Human) CVCL_1070
8MGBA cells Brain Homo sapiens (Human) CVCL_1052
42MGBA cells Brain Homo sapiens (Human) CVCL_1798
In Vivo Model BALB/c nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 CCK-8 assay
Mechanism Description PLX4720 suppresses MEK-ERK phosphorylation and cell proliferation in MA cells containing BRAFV600E mutation.
Preclinical Drug(s)
8 drug(s) in total
Click to Show/Hide the Full List of Drugs
AGI-5198
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Key Molecule: Oxalosuccinate decarboxylase (IDH1) [13]
Sensitive Disease FGFR-tacc positive glioblastoma [ICD-11: 2A00.01]
Sensitive Drug AGI-5198
 Drug Info 
Molecule Alteration Missense mutation
p.R132H (c.395G>A)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.65  Å
PDB: 6BKX
Mutant Type Structure Method: X-ray diffraction Resolution: 1.88  Å
PDB: 4UMX
   Download The Information of Sequence       Download The Structure File   
RMSD: 3.46
TM score: 0.85834
Amino acid change:
R132H
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
M
M
S
S
K
K
K
K
I
I
S
S
G
G
G
G
S
S
10
|
V
V
V
V
E
E
M
M
Q
Q
G
G
D
D
E
E
M
M
T
T
20
|
R
R
I
I
I
I
W
W
E
E
L
L
I
I
K
K
E
E
K
K
30
|
L
L
I
I
F
F
P
P
Y
Y
V
V
E
E
L
L
D
D
L
L
40
|
H
H
S
S
Y
Y
D
D
L
L
G
G
I
I
E
E
N
N
R
R
50
|
D
D
A
A
T
T
N
N
D
D
Q
Q
V
V
T
T
K
K
D
D
60
|
A
A
A
A
E
E
A
A
I
I
K
K
K
K
H
H
N
N
V
V
70
|
G
G
V
V
K
K
C
C
A
A
T
T
I
I
T
T
P
P
D
D
80
|
E
E
K
K
R
R
V
V
E
E
E
E
F
F
K
K
L
L
K
K
90
|
Q
Q
M
M
W
W
K
K
S
S
P
P
N
N
G
G
T
T
I
I
100
|
R
R
N
N
I
I
L
L
G
G
G
G
T
T
V
V
F
F
R
R
110
|
E
E
A
A
I
I
I
I
C
C
K
K
N
N
I
I
P
P
R
R
120
|
L
L
V
V
S
S
G
G
W
W
V
V
K
K
P
P
I
I
I
I
130
|
I
I
G
G
R
H
H
H
A
A
Y
Y
G
G
D
D
Q
Q
Y
Y
140
|
R
R
A
A
T
T
D
D
F
F
V
V
V
V
P
P
G
G
P
P
150
|
G
G
K
K
V
V
E
E
I
I
T
T
Y
Y
T
T
P
P
S
S
160
|
D
D
G
G
T
T
Q
Q
K
K
V
V
T
T
Y
Y
L
L
V
V
170
|
H
H
N
N
F
F
E
E
E
E
G
G
G
G
G
G
V
V
A
A
180
|
M
M
G
G
M
M
Y
Y
N
N
Q
Q
D
D
K
K
S
S
I
I
190
|
E
E
D
D
F
F
A
A
H
H
S
S
S
S
F
F
Q
Q
M
M
200
|
A
A
L
L
S
S
K
K
G
G
W
W
P
P
L
L
Y
Y
L
L
210
|
S
S
T
T
K
K
N
N
T
T
I
I
L
L
K
K
K
K
Y
Y
220
|
D
D
G
G
R
R
F
F
K
K
D
D
I
I
F
F
Q
Q
E
E
230
|
I
I
Y
Y
D
D
K
K
Q
Q
Y
Y
K
K
S
S
Q
Q
F
F
240
|
E
E
A
A
Q
Q
K
K
I
I
W
W
Y
Y
E
E
H
H
R
R
250
|
L
L
I
I
D
D
D
D
M
M
V
V
A
A
Q
Q
A
A
M
M
260
|
K
K
S
S
E
E
G
G
G
G
F
F
I
I
W
W
A
A
C
C
270
|
K
K
N
N
Y
Y
D
D
G
G
D
D
V
V
Q
Q
S
S
D
D
280
|
S
S
V
V
A
A
Q
Q
G
G
Y
Y
G
G
S
S
L
L
G
G
290
|
M
M
M
M
T
T
S
S
V
V
L
L
V
V
C
C
P
P
D
D
300
|
G
G
K
K
T
T
V
V
E
E
A
A
E
E
A
A
A
A
H
H
310
|
G
G
T
T
V
V
T
T
R
R
H
H
Y
Y
R
R
M
M
Y
Y
320
|
Q
Q
K
K
G
G
Q
Q
E
E
T
T
S
S
T
T
N
N
P
P
330
|
I
I
A
A
S
S
I
I
F
F
A
A
W
W
T
T
R
R
G
G
340
|
L
L
A
A
H
H
R
R
A
A
K
K
L
L
D
D
N
N
N
N
350
|
K
K
E
E
L
L
A
A
F
F
F
F
A
A
N
N
A
A
L
L
360
|
E
E
E
E
V
V
S
S
I
I
E
E
T
T
I
I
E
E
A
A
370
|
G
G
F
F
M
M
T
T
K
K
D
D
L
L
A
A
A
A
C
C
380
|
I
I
K
K
G
G
L
L
P
P
N
N
V
V
Q
Q
R
R
S
S
390
|
D
D
Y
Y
L
L
N
N
T
T
F
F
E
E
F
F
M
M
D
D
400
|
K
K
L
L
G
G
E
E
N
N
L
L
K
K
I
I
K
K
L
L
410
|
A
A
Q
Q
A
A
K
K
L
L
S
S
L
L
E
E
H
H
H
H
420
|
H
H
H
H
H
H
H
H
H
H
H
H
Click to Show/Hide the Structure
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model TS676 cells Brain Homo sapiens (Human) CVCL_A5HX
TS603 cells Brain Homo sapiens (Human) CVCL_A5HW
TS516 cells Brain Homo sapiens (Human) CVCL_A5HY
In Vivo Model SCID mouse xenograft model Mus musculus
Experiment for
Drug Resistance		 Soft agar assay
Mechanism Description The missense mutation p.R132H (c.395G>A) in gene IDH1 cause the sensitivity of AGI-5198 by aberration of the drug's therapeutic target
Key Molecule: Oxalosuccinate decarboxylase (IDH1) [13]
Sensitive Disease Brain glioma [ICD-11: 2A00.0]
Sensitive Drug AGI-5198
 Drug Info 
Molecule Alteration Missense mutation
p.R132H (c.395G>A)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.65  Å
PDB: 6BKX
Mutant Type Structure Method: X-ray diffraction Resolution: 1.88  Å
PDB: 4UMX
   Download The Information of Sequence       Download The Structure File   
RMSD: 3.46
TM score: 0.85834
Amino acid change:
R132H
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
M
M
S
S
K
K
K
K
I
I
S
S
G
G
G
G
S
S
10
|
V
V
V
V
E
E
M
M
Q
Q
G
G
D
D
E
E
M
M
T
T
20
|
R
R
I
I
I
I
W
W
E
E
L
L
I
I
K
K
E
E
K
K
30
|
L
L
I
I
F
F
P
P
Y
Y
V
V
E
E
L
L
D
D
L
L
40
|
H
H
S
S
Y
Y
D
D
L
L
G
G
I
I
E
E
N
N
R
R
50
|
D
D
A
A
T
T
N
N
D
D
Q
Q
V
V
T
T
K
K
D
D
60
|
A
A
A
A
E
E
A
A
I
I
K
K
K
K
H
H
N
N
V
V
70
|
G
G
V
V
K
K
C
C
A
A
T
T
I
I
T
T
P
P
D
D
80
|
E
E
K
K
R
R
V
V
E
E
E
E
F
F
K
K
L
L
K
K
90
|
Q
Q
M
M
W
W
K
K
S
S
P
P
N
N
G
G
T
T
I
I
100
|
R
R
N
N
I
I
L
L
G
G
G
G
T
T
V
V
F
F
R
R
110
|
E
E
A
A
I
I
I
I
C
C
K
K
N
N
I
I
P
P
R
R
120
|
L
L
V
V
S
S
G
G
W
W
V
V
K
K
P
P
I
I
I
I
130
|
I
I
G
G
R
H
H
H
A
A
Y
Y
G
G
D
D
Q
Q
Y
Y
140
|
R
R
A
A
T
T
D
D
F
F
V
V
V
V
P
P
G
G
P
P
150
|
G
G
K
K
V
V
E
E
I
I
T
T
Y
Y
T
T
P
P
S
S
160
|
D
D
G
G
T
T
Q
Q
K
K
V
V
T
T
Y
Y
L
L
V
V
170
|
H
H
N
N
F
F
E
E
E
E
G
G
G
G
G
G
V
V
A
A
180
|
M
M
G
G
M
M
Y
Y
N
N
Q
Q
D
D
K
K
S
S
I
I
190
|
E
E
D
D
F
F
A
A
H
H
S
S
S
S
F
F
Q
Q
M
M
200
|
A
A
L
L
S
S
K
K
G
G
W
W
P
P
L
L
Y
Y
L
L
210
|
S
S
T
T
K
K
N
N
T
T
I
I
L
L
K
K
K
K
Y
Y
220
|
D
D
G
G
R
R
F
F
K
K
D
D
I
I
F
F
Q
Q
E
E
230
|
I
I
Y
Y
D
D
K
K
Q
Q
Y
Y
K
K
S
S
Q
Q
F
F
240
|
E
E
A
A
Q
Q
K
K
I
I
W
W
Y
Y
E
E
H
H
R
R
250
|
L
L
I
I
D
D
D
D
M
M
V
V
A
A
Q
Q
A
A
M
M
260
|
K
K
S
S
E
E
G
G
G
G
F
F
I
I
W
W
A
A
C
C
270
|
K
K
N
N
Y
Y
D
D
G
G
D
D
V
V
Q
Q
S
S
D
D
280
|
S
S
V
V
A
A
Q
Q
G
G
Y
Y
G
G
S
S
L
L
G
G
290
|
M
M
M
M
T
T
S
S
V
V
L
L
V
V
C
C
P
P
D
D
300
|
G
G
K
K
T
T
V
V
E
E
A
A
E
E
A
A
A
A
H
H
310
|
G
G
T
T
V
V
T
T
R
R
H
H
Y
Y
R
R
M
M
Y
Y
320
|
Q
Q
K
K
G
G
Q
Q
E
E
T
T
S
S
T
T
N
N
P
P
330
|
I
I
A
A
S
S
I
I
F
F
A
A
W
W
T
T
R
R
G
G
340
|
L
L
A
A
H
H
R
R
A
A
K
K
L
L
D
D
N
N
N
N
350
|
K
K
E
E
L
L
A
A
F
F
F
F
A
A
N
N
A
A
L
L
360
|
E
E
E
E
V
V
S
S
I
I
E
E
T
T
I
I
E
E
A
A
370
|
G
G
F
F
M
M
T
T
K
K
D
D
L
L
A
A
A
A
C
C
380
|
I
I
K
K
G
G
L
L
P
P
N
N
V
V
Q
Q
R
R
S
S
390
|
D
D
Y
Y
L
L
N
N
T
T
F
F
E
E
F
F
M
M
D
D
400
|
K
K
L
L
G
G
E
E
N
N
L
L
K
K
I
I
K
K
L
L
410
|
A
A
Q
Q
A
A
K
K
L
L
S
S
L
L
E
E
H
H
H
H
420
|
H
H
H
H
H
H
H
H
H
H
H
H
Click to Show/Hide the Structure
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model TS676 cells Brain Homo sapiens (Human) CVCL_A5HX
TS603 cells Brain Homo sapiens (Human) CVCL_A5HW
TS516 cells Brain Homo sapiens (Human) CVCL_A5HY
In Vivo Model SCID mouse xenograft model Mus musculus
Experiment for
Drug Resistance		 Soft agar assay
Mechanism Description The missense mutation p.R132H (c.395G>A) in gene IDH1 cause the sensitivity of AGI-5198 by aberration of the drug's therapeutic target
Key Molecule: Oxalosuccinate decarboxylase (IDH1) [13]
Sensitive Disease Brain glioma [ICD-11: 2A00.0]
Sensitive Drug AGI-5198
 Drug Info 
Molecule Alteration Missense mutation
p.R132C (c.394C>T)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.93  Å
PDB: 5GIR
Mutant Type Structure Method: X-ray diffraction Resolution: 2.20  Å
PDB: 6IO0
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.64
TM score: 0.30204
Amino acid change:
R132C
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
-
M
-
S
-
K
-
K
-
I
-
S
-
G
-
G
-
S
10
|
-
V
-
V
-
E
-
M
-
Q
-
G
-
D
-
E
-
M
-
T
20
|
-
R
-
I
-
I
-
W
-
E
-
L
-
I
-
K
-
E
-
K
30
|
-
L
-
I
-
F
-
P
-
Y
-
V
-
E
-
L
-
D
-
L
40
|
-
H
-
S
-
Y
-
D
-
L
-
G
-
I
-
E
-
N
-
R
50
|
-
D
-
A
-
T
-
N
-
D
-
Q
-
V
-
T
-
K
-
D
60
|
-
A
-
A
-
E
-
A
-
I
-
K
-
K
-
H
-
N
-
V
70
|
-
G
-
V
-
K
-
C
-
A
-
T
-
I
-
T
-
P
-
D
80
|
-
E
-
K
-
R
-
V
-
E
-
E
-
F
-
K
-
L
-
K
90
|
-
Q
-
M
-
W
-
K
-
S
-
P
-
N
-
G
-
T
-
I
100
|
-
R
-
N
-
I
-
L
-
G
-
G
-
T
-
V
-
F
-
R
110
|
-
E
-
A
-
I
-
I
-
C
-
K
-
N
-
I
-
P
-
R
120
|
-
L
-
V
-
S
-
G
-
W
-
V
K
K
P
P
I
I
I
I
130
|
I
I
G
G
S
C
H
H
A
A
Y
Y
G
G
D
D
-
Q
-
Y
140
|
-
R
-
A
-
T
-
D
-
F
-
V
-
V
-
P
-
G
-
P
150
|
-
G
-
K
-
V
-
E
-
I
-
T
-
Y
-
T
-
P
-
S
160
|
-
D
-
G
-
T
-
Q
-
K
-
V
-
T
-
Y
-
L
-
V
170
|
-
H
-
N
-
F
-
E
-
E
-
G
-
G
-
G
-
V
-
A
180
|
-
M
-
G
-
M
-
Y
-
N
-
Q
-
D
-
K
-
S
-
I
190
|
-
E
-
D
-
F
-
A
-
H
-
S
-
S
-
F
-
Q
-
M
200
|
-
A
-
L
-
S
-
K
-
G
-
W
-
P
-
L
-
Y
-
L
210
|
-
S
-
T
-
K
-
N
-
T
-
I
-
L
-
K
-
K
-
Y
220
|
-
D
-
G
-
R
-
F
-
K
-
D
-
I
-
F
-
Q
-
E
230
|
-
I
-
Y
-
D
-
K
-
Q
-
Y
-
K
-
S
-
Q
-
F
240
|
-
E
-
A
-
Q
-
K
-
I
-
W
-
Y
-
E
-
H
-
R
250
|
-
L
-
I
-
D
-
D
-
M
-
V
-
A
-
Q
-
A
-
M
260
|
-
K
-
S
-
E
-
G
-
G
-
F
-
I
-
W
-
A
-
C
270
|
-
K
-
N
-
Y
-
D
-
G
-
D
-
V
-
Q
-
S
-
D
280
|
-
S
-
V
-
A
-
Q
-
G
-
Y
-
G
-
S
-
L
-
G
290
|
-
M
-
M
-
T
-
S
-
V
-
L
-
V
-
C
-
P
-
D
300
|
-
G
-
K
-
T
-
V
-
E
-
A
-
E
-
A
-
A
-
H
310
|
-
G
-
T
-
V
-
T
-
R
-
H
-
Y
-
R
-
M
-
Y
320
|
-
Q
-
K
-
G
-
Q
-
E
-
T
-
S
-
T
-
N
-
P
330
|
-
I
-
A
-
S
-
I
-
F
-
A
-
W
-
T
-
R
-
G
340
|
-
L
-
A
-
H
-
R
-
A
-
K
-
L
-
D
-
N
-
N
350
|
-
K
-
E
-
L
-
A
-
F
-
F
-
A
-
N
-
A
-
L
360
|
-
E
-
E
-
V
-
S
-
I
-
E
-
T
-
I
-
E
-
A
370
|
-
G
-
F
-
M
-
T
-
K
-
D
-
L
-
A
-
A
-
C
380
|
-
I
-
K
-
G
-
L
-
P
-
N
-
V
-
Q
-
R
-
S
390
|
-
D
-
Y
-
L
-
N
-
T
-
F
-
E
-
F
-
M
-
D
400
|
-
K
-
L
-
G
-
E
-
N
-
L
-
K
-
I
-
K
-
L
410
|
-
A
-
Q
-
A
-
K
-
L
Click to Show/Hide the Structure
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model TS676 cells Brain Homo sapiens (Human) CVCL_A5HX
TS603 cells Brain Homo sapiens (Human) CVCL_A5HW
TS516 cells Brain Homo sapiens (Human) CVCL_A5HY
In Vivo Model SCID mouse xenograft model Mus musculus
Experiment for
Drug Resistance		 Soft agar assay
Mechanism Description The missense mutation p.R132C (c.394C>T) in gene IDH1 cause the sensitivity of AGI-5198 by aberration of the drug's therapeutic target
BI-2536
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [11]
Sensitive Disease FGFR-tacc positive glioblastoma [ICD-11: 2A00.01]
Sensitive Drug BI-2536
 Drug Info 
Molecule Alteration Missense mutation
p.V600E (c.1799T>A)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 2.55  Å
PDB: 4E26
Mutant Type Structure Method: X-ray diffraction Resolution: 3.20  Å
PDB: 4G9R
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.53
TM score: 0.95765
Amino acid change:
V600E
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
420
|
M
M
D
D
R
R
G
G
S
S
H
H
H
H
H
H
H
H
H
H
430
|
H
H
G
G
S
S
E
E
D
D
R
R
N
N
R
R
M
M
K
K
440
|
T
T
L
L
G
G
R
R
R
R
D
D
S
S
S
S
D
D
D
D
450
|
W
W
E
E
I
I
P
P
D
D
G
G
Q
Q
I
I
T
T
V
V
460
|
G
G
Q
Q
R
R
I
I
G
G
S
S
G
G
S
S
F
F
G
G
470
|
T
T
V
V
Y
Y
K
K
G
G
K
K
W
W
H
H
G
G
D
D
480
|
V
V
A
A
V
V
K
K
M
M
L
L
N
N
V
V
T
T
A
A
490
|
P
P
T
T
P
P
Q
Q
Q
Q
L
L
Q
Q
A
A
F
F
K
K
500
|
N
N
E
E
V
V
G
G
V
V
L
L
R
R
K
K
T
T
R
R
510
|
H
H
V
V
N
N
I
I
L
L
L
L
F
F
M
M
G
G
Y
Y
520
|
S
S
T
T
K
K
P
P
Q
Q
L
L
A
A
I
I
V
V
T
T
530
|
Q
Q
W
W
C
C
E
E
G
G
S
S
S
S
L
L
Y
Y
H
H
540
|
H
H
L
L
H
H
I
I
I
I
E
E
T
T
K
K
F
F
E
E
550
|
M
M
I
I
K
K
L
L
I
I
D
D
I
I
A
A
R
R
Q
Q
560
|
T
T
A
A
Q
Q
G
G
M
M
D
D
Y
Y
L
L
H
H
A
A
570
|
K
K
S
S
I
I
I
I
H
H
R
R
D
D
L
L
K
K
S
S
580
|
N
N
N
N
I
I
F
F
L
L
H
H
E
E
D
D
L
L
T
T
590
|
V
V
K
K
I
I
G
G
D
D
F
F
G
G
L
L
A
A
T
T
600
|
V
E
K
K
S
S
R
R
W
W
S
S
G
G
S
S
H
H
Q
Q
610
|
F
F
E
E
Q
Q
L
L
S
S
G
G
S
S
I
I
L
L
W
W
620
|
M
M
A
A
P
P
E
E
V
V
I
I
R
R
M
M
Q
Q
D
D
630
|
K
K
N
N
P
P
Y
Y
S
S
F
F
Q
Q
S
S
D
D
V
V
640
|
Y
Y
A
A
F
F
G
G
I
I
V
V
L
L
Y
Y
E
E
L
L
650
|
M
M
T
T
G
G
Q
Q
L
L
P
P
Y
Y
S
S
N
N
I
I
660
|
N
N
N
N
R
R
D
D
Q
Q
I
I
I
I
F
F
M
M
V
V
670
|
G
G
R
R
G
G
Y
Y
L
L
S
S
P
P
D
D
L
L
S
S
680
|
K
K
V
V
R
R
S
S
N
N
C
C
P
P
K
K
A
A
M
M
690
|
K
K
R
R
L
L
M
M
A
A
E
E
C
C
L
L
K
K
K
K
700
|
K
K
R
R
D
D
E
E
R
R
P
P
L
L
F
F
P
P
Q
Q
710
|
I
I
L
L
A
A
S
S
I
I
E
E
L
L
L
L
A
A
R
R
720
|
S
S
L
L
P
P
K
K
I
I
H
H
R
R
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
In Vitro Model GBM cells Brain Homo sapiens (Human) N.A.
In Vivo Model Athymic mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 qPCR
Experiment for
Drug Resistance		 Alamar blue proliferation assay
BPTES
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Oxalosuccinate decarboxylase (IDH1) [14]
Sensitive Disease Brain glioma [ICD-11: 2A00.0]
Sensitive Drug BPTES
 Drug Info 
Molecule Alteration Missense mutation
p.R132H (c.395G>A)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.65  Å
PDB: 6BKX
Mutant Type Structure Method: X-ray diffraction Resolution: 1.88  Å
PDB: 4UMX
   Download The Information of Sequence       Download The Structure File   
RMSD: 3.46
TM score: 0.85834
Amino acid change:
R132H
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
M
M
S
S
K
K
K
K
I
I
S
S
G
G
G
G
S
S
10
|
V
V
V
V
E
E
M
M
Q
Q
G
G
D
D
E
E
M
M
T
T
20
|
R
R
I
I
I
I
W
W
E
E
L
L
I
I
K
K
E
E
K
K
30
|
L
L
I
I
F
F
P
P
Y
Y
V
V
E
E
L
L
D
D
L
L
40
|
H
H
S
S
Y
Y
D
D
L
L
G
G
I
I
E
E
N
N
R
R
50
|
D
D
A
A
T
T
N
N
D
D
Q
Q
V
V
T
T
K
K
D
D
60
|
A
A
A
A
E
E
A
A
I
I
K
K
K
K
H
H
N
N
V
V
70
|
G
G
V
V
K
K
C
C
A
A
T
T
I
I
T
T
P
P
D
D
80
|
E
E
K
K
R
R
V
V
E
E
E
E
F
F
K
K
L
L
K
K
90
|
Q
Q
M
M
W
W
K
K
S
S
P
P
N
N
G
G
T
T
I
I
100
|
R
R
N
N
I
I
L
L
G
G
G
G
T
T
V
V
F
F
R
R
110
|
E
E
A
A
I
I
I
I
C
C
K
K
N
N
I
I
P
P
R
R
120
|
L
L
V
V
S
S
G
G
W
W
V
V
K
K
P
P
I
I
I
I
130
|
I
I
G
G
R
H
H
H
A
A
Y
Y
G
G
D
D
Q
Q
Y
Y
140
|
R
R
A
A
T
T
D
D
F
F
V
V
V
V
P
P
G
G
P
P
150
|
G
G
K
K
V
V
E
E
I
I
T
T
Y
Y
T
T
P
P
S
S
160
|
D
D
G
G
T
T
Q
Q
K
K
V
V
T
T
Y
Y
L
L
V
V
170
|
H
H
N
N
F
F
E
E
E
E
G
G
G
G
G
G
V
V
A
A
180
|
M
M
G
G
M
M
Y
Y
N
N
Q
Q
D
D
K
K
S
S
I
I
190
|
E
E
D
D
F
F
A
A
H
H
S
S
S
S
F
F
Q
Q
M
M
200
|
A
A
L
L
S
S
K
K
G
G
W
W
P
P
L
L
Y
Y
L
L
210
|
S
S
T
T
K
K
N
N
T
T
I
I
L
L
K
K
K
K
Y
Y
220
|
D
D
G
G
R
R
F
F
K
K
D
D
I
I
F
F
Q
Q
E
E
230
|
I
I
Y
Y
D
D
K
K
Q
Q
Y
Y
K
K
S
S
Q
Q
F
F
240
|
E
E
A
A
Q
Q
K
K
I
I
W
W
Y
Y
E
E
H
H
R
R
250
|
L
L
I
I
D
D
D
D
M
M
V
V
A
A
Q
Q
A
A
M
M
260
|
K
K
S
S
E
E
G
G
G
G
F
F
I
I
W
W
A
A
C
C
270
|
K
K
N
N
Y
Y
D
D
G
G
D
D
V
V
Q
Q
S
S
D
D
280
|
S
S
V
V
A
A
Q
Q
G
G
Y
Y
G
G
S
S
L
L
G
G
290
|
M
M
M
M
T
T
S
S
V
V
L
L
V
V
C
C
P
P
D
D
300
|
G
G
K
K
T
T
V
V
E
E
A
A
E
E
A
A
A
A
H
H
310
|
G
G
T
T
V
V
T
T
R
R
H
H
Y
Y
R
R
M
M
Y
Y
320
|
Q
Q
K
K
G
G
Q
Q
E
E
T
T
S
S
T
T
N
N
P
P
330
|
I
I
A
A
S
S
I
I
F
F
A
A
W
W
T
T
R
R
G
G
340
|
L
L
A
A
H
H
R
R
A
A
K
K
L
L
D
D
N
N
N
N
350
|
K
K
E
E
L
L
A
A
F
F
F
F
A
A
N
N
A
A
L
L
360
|
E
E
E
E
V
V
S
S
I
I
E
E
T
T
I
I
E
E
A
A
370
|
G
G
F
F
M
M
T
T
K
K
D
D
L
L
A
A
A
A
C
C
380
|
I
I
K
K
G
G
L
L
P
P
N
N
V
V
Q
Q
R
R
S
S
390
|
D
D
Y
Y
L
L
N
N
T
T
F
F
E
E
F
F
M
M
D
D
400
|
K
K
L
L
G
G
E
E
N
N
L
L
K
K
I
I
K
K
L
L
410
|
A
A
Q
Q
A
A
K
K
L
L
S
S
L
L
E
E
H
H
H
H
420
|
H
H
H
H
H
H
H
H
H
H
H
H
Click to Show/Hide the Structure
Experimental Note Revealed Based on the Cell Line Data
Experiment for
Drug Resistance		 3H-thymidine incorporation assay
Mechanism Description The missense mutation p.R132H (c.395G>A) in gene IDH1 cause the sensitivity of BPTES by unusual activation of pro-survival pathway
Everolimus/Binimetinib
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: GTPase Nras (NRAS) [15]
Sensitive Disease Neuroblastoma [ICD-11: 2A00.11]
Sensitive Drug Everolimus/Binimetinib
 Drug Info 
Molecule Alteration Missense mutation
p.Q61K (c.181C>A)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.59  Å
PDB: 8TBI
Mutant Type Structure Method: X-ray diffraction Resolution: 1.74  Å
PDB: 8VM2
   Download The Information of Sequence       Download The Structure File   
RMSD: 0.75
TM score: 0.98025
Amino acid change:
Q61K
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
-
M
-
H
-
H
-
H
-
H
-
H
-
H
-10
|
-
S
-
S
-
G
-
R
-
E
-
N
-
L
-
Y
-
F
-
Q
0
|
S
G
M
M
T
T
E
E
Y
Y
K
K
L
L
V
V
V
V
V
V
10
|
G
G
A
A
G
G
G
G
V
V
G
G
K
K
S
S
A
A
L
L
20
|
T
T
I
I
Q
Q
L
L
I
I
Q
Q
N
N
H
H
F
F
V
V
30
|
D
D
E
E
Y
Y
D
D
P
P
T
T
I
I
E
E
D
D
S
S
40
|
Y
Y
R
R
K
K
Q
Q
V
V
V
V
I
I
D
D
G
G
E
E
50
|
T
T
C
C
L
L
L
L
D
D
I
I
L
L
D
D
T
T
A
A
60
|
G
G
Q
K
E
E
E
E
Y
Y
S
S
A
A
M
M
R
R
D
D
70
|
Q
Q
Y
Y
M
M
R
R
T
T
G
G
E
E
G
G
F
F
L
L
80
|
C
C
V
V
F
F
A
A
I
I
N
N
N
N
S
S
K
K
S
S
90
|
F
F
A
A
D
D
I
I
N
N
L
L
Y
Y
R
R
E
E
Q
Q
100
|
I
I
K
K
R
R
V
V
K
K
D
D
S
S
D
D
D
D
V
V
110
|
P
P
M
M
V
V
L
L
V
V
G
G
N
N
K
K
C
C
D
D
120
|
L
L
P
P
T
T
R
R
T
T
V
V
D
D
T
T
K
K
Q
Q
130
|
A
A
H
H
E
E
L
L
A
A
K
K
S
S
Y
Y
G
G
I
I
140
|
P
P
F
F
I
I
E
E
T
T
S
S
A
A
K
K
T
T
R
R
150
|
Q
Q
G
G
V
V
E
E
D
D
A
A
F
F
Y
Y
T
T
L
L
160
|
V
V
R
R
E
E
I
I
R
R
Q
Q
Y
Y
R
R
M
M
K
K
170
|
K
K
L
L
N
N
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation PI3K/mTOR signaling pathway Inhibition hsa04151
In Vitro Model Sk-N-AS cells Adrenal Homo sapiens (Human) CVCL_1700
SH-SY5Y cells Abdomen Homo sapiens (Human) CVCL_0019
NGP cells Lung Homo sapiens (Human) CVCL_2141
CHP-212 cells Brain Homo sapiens (Human) CVCL_1125
CHP-134 cells Adrenal gland Homo sapiens (Human) CVCL_1124
Experiment for
Molecule Alteration		 Western blot analysis; PCR
Experiment for
Drug Resistance		 Promega assay; FACS assay
Mechanism Description Combination of mTOR and MEK inhibitors synergistically inhibit downstream signaling and cell growth of NRAS mutant cell lines.
Everolimus/PLX4720
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [16]
Sensitive Disease Brain glioma [ICD-11: 2A00.0]
Sensitive Drug Everolimus/PLX4720
 Drug Info 
Molecule Alteration Missense mutation
p.V600E (c.1799T>A)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 2.55  Å
PDB: 4E26
Mutant Type Structure Method: X-ray diffraction Resolution: 3.20  Å
PDB: 4G9R
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.53
TM score: 0.95765
Amino acid change:
V600E
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
420
|
M
M
D
D
R
R
G
G
S
S
H
H
H
H
H
H
H
H
H
H
430
|
H
H
G
G
S
S
E
E
D
D
R
R
N
N
R
R
M
M
K
K
440
|
T
T
L
L
G
G
R
R
R
R
D
D
S
S
S
S
D
D
D
D
450
|
W
W
E
E
I
I
P
P
D
D
G
G
Q
Q
I
I
T
T
V
V
460
|
G
G
Q
Q
R
R
I
I
G
G
S
S
G
G
S
S
F
F
G
G
470
|
T
T
V
V
Y
Y
K
K
G
G
K
K
W
W
H
H
G
G
D
D
480
|
V
V
A
A
V
V
K
K
M
M
L
L
N
N
V
V
T
T
A
A
490
|
P
P
T
T
P
P
Q
Q
Q
Q
L
L
Q
Q
A
A
F
F
K
K
500
|
N
N
E
E
V
V
G
G
V
V
L
L
R
R
K
K
T
T
R
R
510
|
H
H
V
V
N
N
I
I
L
L
L
L
F
F
M
M
G
G
Y
Y
520
|
S
S
T
T
K
K
P
P
Q
Q
L
L
A
A
I
I
V
V
T
T
530
|
Q
Q
W
W
C
C
E
E
G
G
S
S
S
S
L
L
Y
Y
H
H
540
|
H
H
L
L
H
H
I
I
I
I
E
E
T
T
K
K
F
F
E
E
550
|
M
M
I
I
K
K
L
L
I
I
D
D
I
I
A
A
R
R
Q
Q
560
|
T
T
A
A
Q
Q
G
G
M
M
D
D
Y
Y
L
L
H
H
A
A
570
|
K
K
S
S
I
I
I
I
H
H
R
R
D
D
L
L
K
K
S
S
580
|
N
N
N
N
I
I
F
F
L
L
H
H
E
E
D
D
L
L
T
T
590
|
V
V
K
K
I
I
G
G
D
D
F
F
G
G
L
L
A
A
T
T
600
|
V
E
K
K
S
S
R
R
W
W
S
S
G
G
S
S
H
H
Q
Q
610
|
F
F
E
E
Q
Q
L
L
S
S
G
G
S
S
I
I
L
L
W
W
620
|
M
M
A
A
P
P
E
E
V
V
I
I
R
R
M
M
Q
Q
D
D
630
|
K
K
N
N
P
P
Y
Y
S
S
F
F
Q
Q
S
S
D
D
V
V
640
|
Y
Y
A
A
F
F
G
G
I
I
V
V
L
L
Y
Y
E
E
L
L
650
|
M
M
T
T
G
G
Q
Q
L
L
P
P
Y
Y
S
S
N
N
I
I
660
|
N
N
N
N
R
R
D
D
Q
Q
I
I
I
I
F
F
M
M
V
V
670
|
G
G
R
R
G
G
Y
Y
L
L
S
S
P
P
D
D
L
L
S
S
680
|
K
K
V
V
R
R
S
S
N
N
C
C
P
P
K
K
A
A
M
M
690
|
K
K
R
R
L
L
M
M
A
A
E
E
C
C
L
L
K
K
K
K
700
|
K
K
R
R
D
D
E
E
R
R
P
P
L
L
F
F
P
P
Q
Q
710
|
I
I
L
L
A
A
S
S
I
I
E
E
L
L
L
L
A
A
R
R
720
|
S
S
L
L
P
P
K
K
I
I
H
H
R
R
Click to Show/Hide the Structure
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation BRAF/MEK/MAPK signaling pathway Inhibition hsa04010
In Vitro Model DBTRG cells Brain Homo sapiens (Human) CVCL_1169
SF9427 cells N.A. Homo sapiens (Human) N.A.
SF8628 cells Brain Homo sapiens (Human) CVCL_IT46
SF188 cells Brain Homo sapiens (Human) CVCL_6948
BT40 cells N.A. Homo sapiens (Human) N.A.
AM-38 cells Brain Homo sapiens (Human) CVCL_1070
In Vivo Model NSG mouse PDX model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 Promega assay
Mechanism Description Combination therapy in BRAFV600E-mutant human glioma cells enhances cell cycle arrest and apoptosis and reduces proliferation compared to monotherapy.
Everolimus/Selumetinib
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [16]
Sensitive Disease Brain glioma [ICD-11: 2A00.0]
Sensitive Drug Everolimus/Selumetinib
 Drug Info 
Molecule Alteration Missense mutation
p.V600E (c.1799T>A)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 2.55  Å
PDB: 4E26
Mutant Type Structure Method: X-ray diffraction Resolution: 3.20  Å
PDB: 4G9R
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.53
TM score: 0.95765
Amino acid change:
V600E
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
420
|
M
M
D
D
R
R
G
G
S
S
H
H
H
H
H
H
H
H
H
H
430
|
H
H
G
G
S
S
E
E
D
D
R
R
N
N
R
R
M
M
K
K
440
|
T
T
L
L
G
G
R
R
R
R
D
D
S
S
S
S
D
D
D
D
450
|
W
W
E
E
I
I
P
P
D
D
G
G
Q
Q
I
I
T
T
V
V
460
|
G
G
Q
Q
R
R
I
I
G
G
S
S
G
G
S
S
F
F
G
G
470
|
T
T
V
V
Y
Y
K
K
G
G
K
K
W
W
H
H
G
G
D
D
480
|
V
V
A
A
V
V
K
K
M
M
L
L
N
N
V
V
T
T
A
A
490
|
P
P
T
T
P
P
Q
Q
Q
Q
L
L
Q
Q
A
A
F
F
K
K
500
|
N
N
E
E
V
V
G
G
V
V
L
L
R
R
K
K
T
T
R
R
510
|
H
H
V
V
N
N
I
I
L
L
L
L
F
F
M
M
G
G
Y
Y
520
|
S
S
T
T
K
K
P
P
Q
Q
L
L
A
A
I
I
V
V
T
T
530
|
Q
Q
W
W
C
C
E
E
G
G
S
S
S
S
L
L
Y
Y
H
H
540
|
H
H
L
L
H
H
I
I
I
I
E
E
T
T
K
K
F
F
E
E
550
|
M
M
I
I
K
K
L
L
I
I
D
D
I
I
A
A
R
R
Q
Q
560
|
T
T
A
A
Q
Q
G
G
M
M
D
D
Y
Y
L
L
H
H
A
A
570
|
K
K
S
S
I
I
I
I
H
H
R
R
D
D
L
L
K
K
S
S
580
|
N
N
N
N
I
I
F
F
L
L
H
H
E
E
D
D
L
L
T
T
590
|
V
V
K
K
I
I
G
G
D
D
F
F
G
G
L
L
A
A
T
T
600
|
V
E
K
K
S
S
R
R
W
W
S
S
G
G
S
S
H
H
Q
Q
610
|
F
F
E
E
Q
Q
L
L
S
S
G
G
S
S
I
I
L
L
W
W
620
|
M
M
A
A
P
P
E
E
V
V
I
I
R
R
M
M
Q
Q
D
D
630
|
K
K
N
N
P
P
Y
Y
S
S
F
F
Q
Q
S
S
D
D
V
V
640
|
Y
Y
A
A
F
F
G
G
I
I
V
V
L
L
Y
Y
E
E
L
L
650
|
M
M
T
T
G
G
Q
Q
L
L
P
P
Y
Y
S
S
N
N
I
I
660
|
N
N
N
N
R
R
D
D
Q
Q
I
I
I
I
F
F
M
M
V
V
670
|
G
G
R
R
G
G
Y
Y
L
L
S
S
P
P
D
D
L
L
S
S
680
|
K
K
V
V
R
R
S
S
N
N
C
C
P
P
K
K
A
A
M
M
690
|
K
K
R
R
L
L
M
M
A
A
E
E
C
C
L
L
K
K
K
K
700
|
K
K
R
R
D
D
E
E
R
R
P
P
L
L
F
F
P
P
Q
Q
710
|
I
I
L
L
A
A
S
S
I
I
E
E
L
L
L
L
A
A
R
R
720
|
S
S
L
L
P
P
K
K
I
I
H
H
R
R
Click to Show/Hide the Structure
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation BRAF/MEK/MAPK signaling pathway Inhibition hsa04010
In Vitro Model DBTRG cells Brain Homo sapiens (Human) CVCL_1169
SF9427 cells N.A. Homo sapiens (Human) N.A.
SF8628 cells Brain Homo sapiens (Human) CVCL_IT46
SF188 cells Brain Homo sapiens (Human) CVCL_6948
BT40 cells N.A. Homo sapiens (Human) N.A.
AM-38 cells Brain Homo sapiens (Human) CVCL_1070
In Vivo Model NSG mouse PDX model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 Promega assay
Mechanism Description Combination therapy in BRAFV600E-mutant human glioma cells enhances cell cycle arrest and apoptosis and reduces proliferation compared to monotherapy.
IDH1 inhibitors
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Key Molecule: Oxalosuccinate decarboxylase (IDH1) [13]
Sensitive Disease Brain glioma [ICD-11: 2A00.0]
Sensitive Drug IDH1 inhibitors
 Drug Info 
Molecule Alteration Missense mutation
p.R132H (c.395G>A)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.65  Å
PDB: 6BKX
Mutant Type Structure Method: X-ray diffraction Resolution: 1.88  Å
PDB: 4UMX
   Download The Information of Sequence       Download The Structure File   
RMSD: 3.46
TM score: 0.85834
Amino acid change:
R132H
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
M
M
S
S
K
K
K
K
I
I
S
S
G
G
G
G
S
S
10
|
V
V
V
V
E
E
M
M
Q
Q
G
G
D
D
E
E
M
M
T
T
20
|
R
R
I
I
I
I
W
W
E
E
L
L
I
I
K
K
E
E
K
K
30
|
L
L
I
I
F
F
P
P
Y
Y
V
V
E
E
L
L
D
D
L
L
40
|
H
H
S
S
Y
Y
D
D
L
L
G
G
I
I
E
E
N
N
R
R
50
|
D
D
A
A
T
T
N
N
D
D
Q
Q
V
V
T
T
K
K
D
D
60
|
A
A
A
A
E
E
A
A
I
I
K
K
K
K
H
H
N
N
V
V
70
|
G
G
V
V
K
K
C
C
A
A
T
T
I
I
T
T
P
P
D
D
80
|
E
E
K
K
R
R
V
V
E
E
E
E
F
F
K
K
L
L
K
K
90
|
Q
Q
M
M
W
W
K
K
S
S
P
P
N
N
G
G
T
T
I
I
100
|
R
R
N
N
I
I
L
L
G
G
G
G
T
T
V
V
F
F
R
R
110
|
E
E
A
A
I
I
I
I
C
C
K
K
N
N
I
I
P
P
R
R
120
|
L
L
V
V
S
S
G
G
W
W
V
V
K
K
P
P
I
I
I
I
130
|
I
I
G
G
R
H
H
H
A
A
Y
Y
G
G
D
D
Q
Q
Y
Y
140
|
R
R
A
A
T
T
D
D
F
F
V
V
V
V
P
P
G
G
P
P
150
|
G
G
K
K
V
V
E
E
I
I
T
T
Y
Y
T
T
P
P
S
S
160
|
D
D
G
G
T
T
Q
Q
K
K
V
V
T
T
Y
Y
L
L
V
V
170
|
H
H
N
N
F
F
E
E
E
E
G
G
G
G
G
G
V
V
A
A
180
|
M
M
G
G
M
M
Y
Y
N
N
Q
Q
D
D
K
K
S
S
I
I
190
|
E
E
D
D
F
F
A
A
H
H
S
S
S
S
F
F
Q
Q
M
M
200
|
A
A
L
L
S
S
K
K
G
G
W
W
P
P
L
L
Y
Y
L
L
210
|
S
S
T
T
K
K
N
N
T
T
I
I
L
L
K
K
K
K
Y
Y
220
|
D
D
G
G
R
R
F
F
K
K
D
D
I
I
F
F
Q
Q
E
E
230
|
I
I
Y
Y
D
D
K
K
Q
Q
Y
Y
K
K
S
S
Q
Q
F
F
240
|
E
E
A
A
Q
Q
K
K
I
I
W
W
Y
Y
E
E
H
H
R
R
250
|
L
L
I
I
D
D
D
D
M
M
V
V
A
A
Q
Q
A
A
M
M
260
|
K
K
S
S
E
E
G
G
G
G
F
F
I
I
W
W
A
A
C
C
270
|
K
K
N
N
Y
Y
D
D
G
G
D
D
V
V
Q
Q
S
S
D
D
280
|
S
S
V
V
A
A
Q
Q
G
G
Y
Y
G
G
S
S
L
L
G
G
290
|
M
M
M
M
T
T
S
S
V
V
L
L
V
V
C
C
P
P
D
D
300
|
G
G
K
K
T
T
V
V
E
E
A
A
E
E
A
A
A
A
H
H
310
|
G
G
T
T
V
V
T
T
R
R
H
H
Y
Y
R
R
M
M
Y
Y
320
|
Q
Q
K
K
G
G
Q
Q
E
E
T
T
S
S
T
T
N
N
P
P
330
|
I
I
A
A
S
S
I
I
F
F
A
A
W
W
T
T
R
R
G
G
340
|
L
L
A
A
H
H
R
R
A
A
K
K
L
L
D
D
N
N
N
N
350
|
K
K
E
E
L
L
A
A
F
F
F
F
A
A
N
N
A
A
L
L
360
|
E
E
E
E
V
V
S
S
I
I
E
E
T
T
I
I
E
E
A
A
370
|
G
G
F
F
M
M
T
T
K
K
D
D
L
L
A
A
A
A
C
C
380
|
I
I
K
K
G
G
L
L
P
P
N
N
V
V
Q
Q
R
R
S
S
390
|
D
D
Y
Y
L
L
N
N
T
T
F
F
E
E
F
F
M
M
D
D
400
|
K
K
L
L
G
G
E
E
N
N
L
L
K
K
I
I
K
K
L
L
410
|
A
A
Q
Q
A
A
K
K
L
L
S
S
L
L
E
E
H
H
H
H
420
|
H
H
H
H
H
H
H
H
H
H
H
H
Click to Show/Hide the Structure
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model TS676 cells Brain Homo sapiens (Human) CVCL_A5HX
TS603 cells Brain Homo sapiens (Human) CVCL_A5HW
TS516 cells Brain Homo sapiens (Human) CVCL_A5HY
In Vivo Model SCID mouse xenograft model Mus musculus
Experiment for
Drug Resistance		 Soft agar assay
Mechanism Description The missense mutation p.R132H (c.395G>A) in gene IDH1 cause the sensitivity of IDH1 inhibitors by aberration of the drug's therapeutic target
SF1126
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: GTPase Hras (HRAS) [17]
Sensitive Disease Brain glioma [ICD-11: 2A00.0]
Sensitive Drug SF1126
 Drug Info 
Molecule Alteration Missense mutation
p.G12V (c.35G>T)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.98  Å
PDB: 7SCW
Mutant Type Structure Method: X-ray diffraction Resolution: 1.96  Å
PDB: 7SCX
   Download The Information of Sequence       Download The Structure File   
RMSD: 0.47
TM score: 0.99104
Amino acid change:
G12V
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
G
-
0
|
S
-
M
M
T
T
E
E
Y
Y
K
K
L
L
V
V
V
V
V
V
10
|
G
G
A
A
G
V
G
G
V
V
G
G
K
K
S
S
A
A
L
L
20
|
T
T
I
I
Q
Q
L
L
I
I
Q
Q
N
N
H
H
F
F
V
V
30
|
D
D
E
E
Y
Y
D
D
P
P
T
T
I
I
E
E
D
D
S
S
40
|
Y
Y
R
R
K
K
Q
Q
V
V
V
V
I
I
D
D
G
G
E
E
50
|
T
T
C
C
L
L
L
L
D
D
I
I
L
L
D
D
T
T
A
A
60
|
G
G
Q
Q
E
E
E
E
Y
Y
S
S
A
A
M
M
R
R
D
D
70
|
Q
Q
Y
Y
M
M
R
R
T
T
G
G
E
E
G
G
F
F
L
L
80
|
C
C
V
V
F
F
A
A
I
I
N
N
N
N
T
T
K
K
S
S
90
|
F
F
E
E
D
D
I
I
H
H
H
H
Y
Y
R
R
E
E
Q
Q
100
|
I
I
K
K
R
R
V
V
K
K
D
D
S
S
E
E
D
D
V
V
110
|
P
P
M
M
V
V
L
L
V
V
G
G
N
N
K
K
S
S
D
D
120
|
L
L
P
P
S
S
R
R
T
T
V
V
D
D
T
T
K
K
Q
Q
130
|
A
A
Q
Q
D
D
L
L
A
A
R
R
S
S
Y
Y
G
G
I
I
140
|
P
P
F
F
I
I
E
E
T
T
S
S
A
A
K
K
T
T
R
R
150
|
Q
Q
G
G
V
V
D
D
D
D
A
A
F
F
Y
Y
T
T
L
L
160
|
V
V
R
R
E
E
I
I
R
R
K
K
H
H
K
K
E
E
K
K
170
|
M
M
S
S
K
K
D
D
G
G
K
K
K
K
K
K
K
K
K
K
180
|
K
K
S
S
K
K
T
T
K
K
C
C
V
V
I
I
M
M
Click to Show/Hide the Structure
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model U87MG glioma cells Brain Homo sapiens (Human) CVCL_0022
In Vivo Model Athymic female (CD-1 Nu/Nu) mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 Kinase-Glo luminescent assay
Investigative Drug(s)
5 drug(s) in total
Click to Show/Hide the Full List of Drugs
AZD3463
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: ALK tyrosine kinase receptor (ALK) [18]
Sensitive Disease Neuroblastoma [ICD-11: 2A00.11]
Sensitive Drug AZD3463
 Drug Info 
Molecule Alteration Missense mutation
p.F1174L (c.3520T>C)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.75  Å
PDB: 3AOX
Mutant Type Structure Method: X-ray diffraction Resolution: 1.75  Å
PDB: 4FNW
   Download The Information of Sequence       Download The Structure File   
RMSD: 0.34
TM score: 0.99391
Amino acid change:
F1174L
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
G
-
M
-
1070
|
Q
-
M
-
E
-
L
-
Q
-
S
-
P
-
E
-
Y
-
K
-
1080
|
L
-
S
-
K
-
L
-
R
R
T
T
S
S
T
T
I
I
M
M
1090
|
T
T
D
D
Y
Y
N
N
P
P
N
N
Y
Y
C
S
F
F
A
A
1100
|
G
G
K
K
T
T
S
S
S
S
I
I
S
S
D
D
L
L
K
K
1110
|
E
E
V
V
P
P
R
R
K
K
N
N
I
I
T
T
L
L
I
I
1120
|
R
R
G
G
L
L
G
G
H
H
G
G
A
A
F
F
G
G
E
E
1130
|
V
V
Y
Y
E
E
G
G
Q
Q
V
V
S
S
G
G
M
M
P
P
1140
|
N
N
D
D
P
P
S
S
P
P
L
L
Q
Q
V
V
A
A
V
V
1150
|
K
K
T
T
L
L
P
P
E
E
V
V
C
C
S
S
E
E
Q
Q
1160
|
D
D
E
E
L
L
D
D
F
F
L
L
M
M
E
E
A
A
L
L
1170
|
I
I
I
I
S
S
K
K
F
L
N
N
H
H
Q
Q
N
N
I
I
1180
|
V
V
R
R
C
C
I
I
G
G
V
V
S
S
L
L
Q
Q
S
S
1190
|
L
L
P
P
R
R
F
F
I
I
L
L
L
L
E
E
L
L
M
M
1200
|
A
A
G
G
G
G
D
D
L
L
K
K
S
S
F
F
L
L
R
R
1210
|
E
E
T
T
R
R
P
P
R
R
P
P
S
S
Q
Q
P
P
S
S
1220
|
S
S
L
L
A
A
M
M
L
L
D
D
L
L
L
L
H
H
V
V
1230
|
A
A
R
R
D
D
I
I
A
A
C
C
G
G
C
C
Q
Q
Y
Y
1240
|
L
L
E
E
E
E
N
N
H
H
F
F
I
I
H
H
R
R
D
D
1250
|
I
I
A
A
A
A
R
R
N
N
C
C
L
L
L
L
T
T
C
C
1260
|
P
P
G
G
P
P
G
G
R
R
V
V
A
A
K
K
I
I
G
G
1270
|
D
D
F
F
G
G
M
M
A
A
R
R
D
D
I
I
Y
Y
R
R
1280
|
A
A
S
S
Y
Y
Y
Y
R
R
K
K
G
G
G
G
C
C
A
A
1290
|
M
M
L
L
P
P
V
V
K
K
W
W
M
M
P
P
P
P
E
E
1300
|
A
A
F
F
M
M
E
E
G
G
I
I
F
F
T
T
S
S
K
K
1310
|
T
T
D
D
T
T
W
W
S
S
F
F
G
G
V
V
L
L
L
L
1320
|
W
W
E
E
I
I
F
F
S
S
L
L
G
G
Y
Y
M
M
P
P
1330
|
Y
Y
P
P
S
S
K
K
S
S
N
N
Q
Q
E
E
V
V
L
L
1340
|
E
E
F
F
V
V
T
T
S
S
G
G
G
G
R
R
M
M
D
D
1350
|
P
P
P
P
K
K
N
N
C
C
P
P
G
G
P
P
V
V
Y
Y
1360
|
R
R
I
I
M
M
T
T
Q
Q
C
C
W
W
Q
Q
H
H
Q
Q
1370
|
P
P
E
E
D
D
R
R
P
P
N
N
F
F
A
A
I
I
I
I
1380
|
L
L
E
E
R
R
I
I
E
E
Y
Y
C
C
T
T
Q
Q
D
D
1390
|
P
P
D
D
V
V
I
I
N
N
T
T
A
A
L
L
P
P
I
I
1400
|
E
E
Y
Y
G
G
P
P
L
L
V
V
E
E
E
E
E
E
E
E
1410
|
K
K
V
-
Click to Show/Hide the Structure
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model IMR-32 cells Abdomen Homo sapiens (Human) CVCL_0346
Sk-N-AS cells Adrenal Homo sapiens (Human) CVCL_1700
SH-SY5Y cells Abdomen Homo sapiens (Human) CVCL_0019
NGP cells Lung Homo sapiens (Human) CVCL_2141
N b-19 cells N.A. Homo sapiens (Human) N.A.
In Vivo Model Orthotopic Mouse Model of NB Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 CCK-8 assay; Colony formation assay
Key Molecule: ALK tyrosine kinase receptor (ALK) [18]
Sensitive Disease Neuroblastoma [ICD-11: 2A00.11]
Sensitive Drug AZD3463
 Drug Info 
Molecule Alteration Missense mutation
p.F1174L (c.3522C>A)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.75  Å
PDB: 3AOX
Mutant Type Structure Method: X-ray diffraction Resolution: 1.75  Å
PDB: 4FNW
   Download The Information of Sequence       Download The Structure File   
RMSD: 0.34
TM score: 0.99391
Amino acid change:
F1174L
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
G
-
M
-
1070
|
Q
-
M
-
E
-
L
-
Q
-
S
-
P
-
E
-
Y
-
K
-
1080
|
L
-
S
-
K
-
L
-
R
R
T
T
S
S
T
T
I
I
M
M
1090
|
T
T
D
D
Y
Y
N
N
P
P
N
N
Y
Y
C
S
F
F
A
A
1100
|
G
G
K
K
T
T
S
S
S
S
I
I
S
S
D
D
L
L
K
K
1110
|
E
E
V
V
P
P
R
R
K
K
N
N
I
I
T
T
L
L
I
I
1120
|
R
R
G
G
L
L
G
G
H
H
G
G
A
A
F
F
G
G
E
E
1130
|
V
V
Y
Y
E
E
G
G
Q
Q
V
V
S
S
G
G
M
M
P
P
1140
|
N
N
D
D
P
P
S
S
P
P
L
L
Q
Q
V
V
A
A
V
V
1150
|
K
K
T
T
L
L
P
P
E
E
V
V
C
C
S
S
E
E
Q
Q
1160
|
D
D
E
E
L
L
D
D
F
F
L
L
M
M
E
E
A
A
L
L
1170
|
I
I
I
I
S
S
K
K
F
L
N
N
H
H
Q
Q
N
N
I
I
1180
|
V
V
R
R
C
C
I
I
G
G
V
V
S
S
L
L
Q
Q
S
S
1190
|
L
L
P
P
R
R
F
F
I
I
L
L
L
L
E
E
L
L
M
M
1200
|
A
A
G
G
G
G
D
D
L
L
K
K
S
S
F
F
L
L
R
R
1210
|
E
E
T
T
R
R
P
P
R
R
P
P
S
S
Q
Q
P
P
S
S
1220
|
S
S
L
L
A
A
M
M
L
L
D
D
L
L
L
L
H
H
V
V
1230
|
A
A
R
R
D
D
I
I
A
A
C
C
G
G
C
C
Q
Q
Y
Y
1240
|
L
L
E
E
E
E
N
N
H
H
F
F
I
I
H
H
R
R
D
D
1250
|
I
I
A
A
A
A
R
R
N
N
C
C
L
L
L
L
T
T
C
C
1260
|
P
P
G
G
P
P
G
G
R
R
V
V
A
A
K
K
I
I
G
G
1270
|
D
D
F
F
G
G
M
M
A
A
R
R
D
D
I
I
Y
Y
R
R
1280
|
A
A
S
S
Y
Y
Y
Y
R
R
K
K
G
G
G
G
C
C
A
A
1290
|
M
M
L
L
P
P
V
V
K
K
W
W
M
M
P
P
P
P
E
E
1300
|
A
A
F
F
M
M
E
E
G
G
I
I
F
F
T
T
S
S
K
K
1310
|
T
T
D
D
T
T
W
W
S
S
F
F
G
G
V
V
L
L
L
L
1320
|
W
W
E
E
I
I
F
F
S
S
L
L
G
G
Y
Y
M
M
P
P
1330
|
Y
Y
P
P
S
S
K
K
S
S
N
N
Q
Q
E
E
V
V
L
L
1340
|
E
E
F
F
V
V
T
T
S
S
G
G
G
G
R
R
M
M
D
D
1350
|
P
P
P
P
K
K
N
N
C
C
P
P
G
G
P
P
V
V
Y
Y
1360
|
R
R
I
I
M
M
T
T
Q
Q
C
C
W
W
Q
Q
H
H
Q
Q
1370
|
P
P
E
E
D
D
R
R
P
P
N
N
F
F
A
A
I
I
I
I
1380
|
L
L
E
E
R
R
I
I
E
E
Y
Y
C
C
T
T
Q
Q
D
D
1390
|
P
P
D
D
V
V
I
I
N
N
T
T
A
A
L
L
P
P
I
I
1400
|
E
E
Y
Y
G
G
P
P
L
L
V
V
E
E
E
E
E
E
E
E
1410
|
K
K
V
-
Click to Show/Hide the Structure
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model IMR-32 cells Abdomen Homo sapiens (Human) CVCL_0346
Sk-N-AS cells Adrenal Homo sapiens (Human) CVCL_1700
SH-SY5Y cells Abdomen Homo sapiens (Human) CVCL_0019
NGP cells Lung Homo sapiens (Human) CVCL_2141
N b-19 cells N.A. Homo sapiens (Human) N.A.
In Vivo Model Orthotopic Mouse Model of NB Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 CCK-8 assay; Colony formation assay
CEP-28122
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Key Molecule: ALK tyrosine kinase receptor (ALK) [19]
Sensitive Disease Neuroblastoma [ICD-11: 2A00.11]
Sensitive Drug CEP-28122
 Drug Info 
Molecule Alteration Missense mutation
p.F1174L (c.3520T>C)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.75  Å
PDB: 3AOX
Mutant Type Structure Method: X-ray diffraction Resolution: 1.75  Å
PDB: 4FNW
   Download The Information of Sequence       Download The Structure File   
RMSD: 0.34
TM score: 0.99391
Amino acid change:
F1174L
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
G
-
M
-
1070
|
Q
-
M
-
E
-
L
-
Q
-
S
-
P
-
E
-
Y
-
K
-
1080
|
L
-
S
-
K
-
L
-
R
R
T
T
S
S
T
T
I
I
M
M
1090
|
T
T
D
D
Y
Y
N
N
P
P
N
N
Y
Y
C
S
F
F
A
A
1100
|
G
G
K
K
T
T
S
S
S
S
I
I
S
S
D
D
L
L
K
K
1110
|
E
E
V
V
P
P
R
R
K
K
N
N
I
I
T
T
L
L
I
I
1120
|
R
R
G
G
L
L
G
G
H
H
G
G
A
A
F
F
G
G
E
E
1130
|
V
V
Y
Y
E
E
G
G
Q
Q
V
V
S
S
G
G
M
M
P
P
1140
|
N
N
D
D
P
P
S
S
P
P
L
L
Q
Q
V
V
A
A
V
V
1150
|
K
K
T
T
L
L
P
P
E
E
V
V
C
C
S
S
E
E
Q
Q
1160
|
D
D
E
E
L
L
D
D
F
F
L
L
M
M
E
E
A
A
L
L
1170
|
I
I
I
I
S
S
K
K
F
L
N
N
H
H
Q
Q
N
N
I
I
1180
|
V
V
R
R
C
C
I
I
G
G
V
V
S
S
L
L
Q
Q
S
S
1190
|
L
L
P
P
R
R
F
F
I
I
L
L
L
L
E
E
L
L
M
M
1200
|
A
A
G
G
G
G
D
D
L
L
K
K
S
S
F
F
L
L
R
R
1210
|
E
E
T
T
R
R
P
P
R
R
P
P
S
S
Q
Q
P
P
S
S
1220
|
S
S
L
L
A
A
M
M
L
L
D
D
L
L
L
L
H
H
V
V
1230
|
A
A
R
R
D
D
I
I
A
A
C
C
G
G
C
C
Q
Q
Y
Y
1240
|
L
L
E
E
E
E
N
N
H
H
F
F
I
I
H
H
R
R
D
D
1250
|
I
I
A
A
A
A
R
R
N
N
C
C
L
L
L
L
T
T
C
C
1260
|
P
P
G
G
P
P
G
G
R
R
V
V
A
A
K
K
I
I
G
G
1270
|
D
D
F
F
G
G
M
M
A
A
R
R
D
D
I
I
Y
Y
R
R
1280
|
A
A
S
S
Y
Y
Y
Y
R
R
K
K
G
G
G
G
C
C
A
A
1290
|
M
M
L
L
P
P
V
V
K
K
W
W
M
M
P
P
P
P
E
E
1300
|
A
A
F
F
M
M
E
E
G
G
I
I
F
F
T
T
S
S
K
K
1310
|
T
T
D
D
T
T
W
W
S
S
F
F
G
G
V
V
L
L
L
L
1320
|
W
W
E
E
I
I
F
F
S
S
L
L
G
G
Y
Y
M
M
P
P
1330
|
Y
Y
P
P
S
S
K
K
S
S
N
N
Q
Q
E
E
V
V
L
L
1340
|
E
E
F
F
V
V
T
T
S
S
G
G
G
G
R
R
M
M
D
D
1350
|
P
P
P
P
K
K
N
N
C
C
P
P
G
G
P
P
V
V
Y
Y
1360
|
R
R
I
I
M
M
T
T
Q
Q
C
C
W
W
Q
Q
H
H
Q
Q
1370
|
P
P
E
E
D
D
R
R
P
P
N
N
F
F
A
A
I
I
I
I
1380
|
L
L
E
E
R
R
I
I
E
E
Y
Y
C
C
T
T
Q
Q
D
D
1390
|
P
P
D
D
V
V
I
I
N
N
T
T
A
A
L
L
P
P
I
I
1400
|
E
E
Y
Y
G
G
P
P
L
L
V
V
E
E
E
E
E
E
E
E
1410
|
K
K
V
-
Click to Show/Hide the Structure
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model SUP-M2 cells Colon Homo sapiens (Human) CVCL_2209
KARPAS-299 cells Peripheral blood Homo sapiens (Human) CVCL_1324
In Vivo Model Mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 MTS assay
Mechanism Description The missense mutation p.F1174L (c.3520T>C) in gene ALK cause the sensitivity of CEP-28122 by aberration of the drug's therapeutic target
Cobimetinib/Vemurafenib
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [20]
Sensitive Disease FGFR-tacc positive glioblastoma [ICD-11: 2A00.01]
Sensitive Drug Cobimetinib/Vemurafenib
 Drug Info 
Molecule Alteration Missense mutation
p.V600E (c.1799T>A)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 2.55  Å
PDB: 4E26
Mutant Type Structure Method: X-ray diffraction Resolution: 3.20  Å
PDB: 4G9R
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.53
TM score: 0.95765
Amino acid change:
V600E
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
420
|
M
M
D
D
R
R
G
G
S
S
H
H
H
H
H
H
H
H
H
H
430
|
H
H
G
G
S
S
E
E
D
D
R
R
N
N
R
R
M
M
K
K
440
|
T
T
L
L
G
G
R
R
R
R
D
D
S
S
S
S
D
D
D
D
450
|
W
W
E
E
I
I
P
P
D
D
G
G
Q
Q
I
I
T
T
V
V
460
|
G
G
Q
Q
R
R
I
I
G
G
S
S
G
G
S
S
F
F
G
G
470
|
T
T
V
V
Y
Y
K
K
G
G
K
K
W
W
H
H
G
G
D
D
480
|
V
V
A
A
V
V
K
K
M
M
L
L
N
N
V
V
T
T
A
A
490
|
P
P
T
T
P
P
Q
Q
Q
Q
L
L
Q
Q
A
A
F
F
K
K
500
|
N
N
E
E
V
V
G
G
V
V
L
L
R
R
K
K
T
T
R
R
510
|
H
H
V
V
N
N
I
I
L
L
L
L
F
F
M
M
G
G
Y
Y
520
|
S
S
T
T
K
K
P
P
Q
Q
L
L
A
A
I
I
V
V
T
T
530
|
Q
Q
W
W
C
C
E
E
G
G
S
S
S
S
L
L
Y
Y
H
H
540
|
H
H
L
L
H
H
I
I
I
I
E
E
T
T
K
K
F
F
E
E
550
|
M
M
I
I
K
K
L
L
I
I
D
D
I
I
A
A
R
R
Q
Q
560
|
T
T
A
A
Q
Q
G
G
M
M
D
D
Y
Y
L
L
H
H
A
A
570
|
K
K
S
S
I
I
I
I
H
H
R
R
D
D
L
L
K
K
S
S
580
|
N
N
N
N
I
I
F
F
L
L
H
H
E
E
D
D
L
L
T
T
590
|
V
V
K
K
I
I
G
G
D
D
F
F
G
G
L
L
A
A
T
T
600
|
V
E
K
K
S
S
R
R
W
W
S
S
G
G
S
S
H
H
Q
Q
610
|
F
F
E
E
Q
Q
L
L
S
S
G
G
S
S
I
I
L
L
W
W
620
|
M
M
A
A
P
P
E
E
V
V
I
I
R
R
M
M
Q
Q
D
D
630
|
K
K
N
N
P
P
Y
Y
S
S
F
F
Q
Q
S
S
D
D
V
V
640
|
Y
Y
A
A
F
F
G
G
I
I
V
V
L
L
Y
Y
E
E
L
L
650
|
M
M
T
T
G
G
Q
Q
L
L
P
P
Y
Y
S
S
N
N
I
I
660
|
N
N
N
N
R
R
D
D
Q
Q
I
I
I
I
F
F
M
M
V
V
670
|
G
G
R
R
G
G
Y
Y
L
L
S
S
P
P
D
D
L
L
S
S
680
|
K
K
V
V
R
R
S
S
N
N
C
C
P
P
K
K
A
A
M
M
690
|
K
K
R
R
L
L
M
M
A
A
E
E
C
C
L
L
K
K
K
K
700
|
K
K
R
R
D
D
E
E
R
R
P
P
L
L
F
F
P
P
Q
Q
710
|
I
I
L
L
A
A
S
S
I
I
E
E
L
L
L
L
A
A
R
R
720
|
S
S
L
L
P
P
K
K
I
I
H
H
R
R
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
NVP-TAE684
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Key Molecule: ALK tyrosine kinase receptor (ALK) [1]
Resistant Disease Neuroblastoma [ICD-11: 2A00.11]
Resistant Drug NVP-TAE684
 Drug Info 
Molecule Alteration Missense mutation
p.F1174L
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.75  Å
PDB: 3AOX
Mutant Type Structure Method: X-ray diffraction Resolution: 1.75  Å
PDB: 4FNW
   Download The Information of Sequence       Download The Structure File   
RMSD: 0.34
TM score: 0.99391
Amino acid change:
F1174L
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
G
-
M
-
1070
|
Q
-
M
-
E
-
L
-
Q
-
S
-
P
-
E
-
Y
-
K
-
1080
|
L
-
S
-
K
-
L
-
R
R
T
T
S
S
T
T
I
I
M
M
1090
|
T
T
D
D
Y
Y
N
N
P
P
N
N
Y
Y
C
S
F
F
A
A
1100
|
G
G
K
K
T
T
S
S
S
S
I
I
S
S
D
D
L
L
K
K
1110
|
E
E
V
V
P
P
R
R
K
K
N
N
I
I
T
T
L
L
I
I
1120
|
R
R
G
G
L
L
G
G
H
H
G
G
A
A
F
F
G
G
E
E
1130
|
V
V
Y
Y
E
E
G
G
Q
Q
V
V
S
S
G
G
M
M
P
P
1140
|
N
N
D
D
P
P
S
S
P
P
L
L
Q
Q
V
V
A
A
V
V
1150
|
K
K
T
T
L
L
P
P
E
E
V
V
C
C
S
S
E
E
Q
Q
1160
|
D
D
E
E
L
L
D
D
F
F
L
L
M
M
E
E
A
A
L
L
1170
|
I
I
I
I
S
S
K
K
F
L
N
N
H
H
Q
Q
N
N
I
I
1180
|
V
V
R
R
C
C
I
I
G
G
V
V
S
S
L
L
Q
Q
S
S
1190
|
L
L
P
P
R
R
F
F
I
I
L
L
L
L
E
E
L
L
M
M
1200
|
A
A
G
G
G
G
D
D
L
L
K
K
S
S
F
F
L
L
R
R
1210
|
E
E
T
T
R
R
P
P
R
R
P
P
S
S
Q
Q
P
P
S
S
1220
|
S
S
L
L
A
A
M
M
L
L
D
D
L
L
L
L
H
H
V
V
1230
|
A
A
R
R
D
D
I
I
A
A
C
C
G
G
C
C
Q
Q
Y
Y
1240
|
L
L
E
E
E
E
N
N
H
H
F
F
I
I
H
H
R
R
D
D
1250
|
I
I
A
A
A
A
R
R
N
N
C
C
L
L
L
L
T
T
C
C
1260
|
P
P
G
G
P
P
G
G
R
R
V
V
A
A
K
K
I
I
G
G
1270
|
D
D
F
F
G
G
M
M
A
A
R
R
D
D
I
I
Y
Y
R
R
1280
|
A
A
S
S
Y
Y
Y
Y
R
R
K
K
G
G
G
G
C
C
A
A
1290
|
M
M
L
L
P
P
V
V
K
K
W
W
M
M
P
P
P
P
E
E
1300
|
A
A
F
F
M
M
E
E
G
G
I
I
F
F
T
T
S
S
K
K
1310
|
T
T
D
D
T
T
W
W
S
S
F
F
G
G
V
V
L
L
L
L
1320
|
W
W
E
E
I
I
F
F
S
S
L
L
G
G
Y
Y
M
M
P
P
1330
|
Y
Y
P
P
S
S
K
K
S
S
N
N
Q
Q
E
E
V
V
L
L
1340
|
E
E
F
F
V
V
T
T
S
S
G
G
G
G
R
R
M
M
D
D
1350
|
P
P
P
P
K
K
N
N
C
C
P
P
G
G
P
P
V
V
Y
Y
1360
|
R
R
I
I
M
M
T
T
Q
Q
C
C
W
W
Q
Q
H
H
Q
Q
1370
|
P
P
E
E
D
D
R
R
P
P
N
N
F
F
A
A
I
I
I
I
1380
|
L
L
E
E
R
R
I
I
E
E
Y
Y
C
C
T
T
Q
Q
D
D
1390
|
P
P
D
D
V
V
I
I
N
N
T
T
A
A
L
L
P
P
I
I
1400
|
E
E
Y
Y
G
G
P
P
L
L
V
V
E
E
E
E
E
E
E
E
1410
|
K
K
V
-
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
Cell Pathway Regulation Cell invasion Activation hsa05200
Cell migration Activation hsa04670
Cell proliferation Activation hsa05200
In Vitro Model NBLW cells Brain Homo sapiens (Human) CVCL_VJ90
NBLW-R cells Brain Homo sapiens (Human) CVCL_VJ91
Experiment for
Molecule Alteration		 Sangersequencing assay; Targeted deep sequencing assay
Experiment for
Drug Resistance		 Array CGH assay
Mechanism Description Analysis of the sensitivity of NBLW and NBLW-R cells to a panel of ALk inhibitors (TAE-684, Crizotinib, Alectinib and Lorlatinib) revealed differences between the paired cell lines, and overall NBLW-R cells with the F1174L mutation were more resistant to ALk inhibitor induced apoptosis compared with NBLW cells.
Temozolomide/Vandetanib
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: Oxalosuccinate decarboxylase (IDH1) [21]
Sensitive Disease FGFR-tacc positive glioblastoma [ICD-11: 2A00.01]
Sensitive Drug Temozolomide/Vandetanib
 Drug Info 
Molecule Alteration Missense mutation
p.R132H (c.395G>A)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.65  Å
PDB: 6BKX
Mutant Type Structure Method: X-ray diffraction Resolution: 1.88  Å
PDB: 4UMX
   Download The Information of Sequence       Download The Structure File   
RMSD: 3.46
TM score: 0.85834
Amino acid change:
R132H
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
M
M
S
S
K
K
K
K
I
I
S
S
G
G
G
G
S
S
10
|
V
V
V
V
E
E
M
M
Q
Q
G
G
D
D
E
E
M
M
T
T
20
|
R
R
I
I
I
I
W
W
E
E
L
L
I
I
K
K
E
E
K
K
30
|
L
L
I
I
F
F
P
P
Y
Y
V
V
E
E
L
L
D
D
L
L
40
|
H
H
S
S
Y
Y
D
D
L
L
G
G
I
I
E
E
N
N
R
R
50
|
D
D
A
A
T
T
N
N
D
D
Q
Q
V
V
T
T
K
K
D
D
60
|
A
A
A
A
E
E
A
A
I
I
K
K
K
K
H
H
N
N
V
V
70
|
G
G
V
V
K
K
C
C
A
A
T
T
I
I
T
T
P
P
D
D
80
|
E
E
K
K
R
R
V
V
E
E
E
E
F
F
K
K
L
L
K
K
90
|
Q
Q
M
M
W
W
K
K
S
S
P
P
N
N
G
G
T
T
I
I
100
|
R
R
N
N
I
I
L
L
G
G
G
G
T
T
V
V
F
F
R
R
110
|
E
E
A
A
I
I
I
I
C
C
K
K
N
N
I
I
P
P
R
R
120
|
L
L
V
V
S
S
G
G
W
W
V
V
K
K
P
P
I
I
I
I
130
|
I
I
G
G
R
H
H
H
A
A
Y
Y
G
G
D
D
Q
Q
Y
Y
140
|
R
R
A
A
T
T
D
D
F
F
V
V
V
V
P
P
G
G
P
P
150
|
G
G
K
K
V
V
E
E
I
I
T
T
Y
Y
T
T
P
P
S
S
160
|
D
D
G
G
T
T
Q
Q
K
K
V
V
T
T
Y
Y
L
L
V
V
170
|
H
H
N
N
F
F
E
E
E
E
G
G
G
G
G
G
V
V
A
A
180
|
M
M
G
G
M
M
Y
Y
N
N
Q
Q
D
D
K
K
S
S
I
I
190
|
E
E
D
D
F
F
A
A
H
H
S
S
S
S
F
F
Q
Q
M
M
200
|
A
A
L
L
S
S
K
K
G
G
W
W
P
P
L
L
Y
Y
L
L
210
|
S
S
T
T
K
K
N
N
T
T
I
I
L
L
K
K
K
K
Y
Y
220
|
D
D
G
G
R
R
F
F
K
K
D
D
I
I
F
F
Q
Q
E
E
230
|
I
I
Y
Y
D
D
K
K
Q
Q
Y
Y
K
K
S
S
Q
Q
F
F
240
|
E
E
A
A
Q
Q
K
K
I
I
W
W
Y
Y
E
E
H
H
R
R
250
|
L
L
I
I
D
D
D
D
M
M
V
V
A
A
Q
Q
A
A
M
M
260
|
K
K
S
S
E
E
G
G
G
G
F
F
I
I
W
W
A
A
C
C
270
|
K
K
N
N
Y
Y
D
D
G
G
D
D
V
V
Q
Q
S
S
D
D
280
|
S
S
V
V
A
A
Q
Q
G
G
Y
Y
G
G
S
S
L
L
G
G
290
|
M
M
M
M
T
T
S
S
V
V
L
L
V
V
C
C
P
P
D
D
300
|
G
G
K
K
T
T
V
V
E
E
A
A
E
E
A
A
A
A
H
H
310
|
G
G
T
T
V
V
T
T
R
R
H
H
Y
Y
R
R
M
M
Y
Y
320
|
Q
Q
K
K
G
G
Q
Q
E
E
T
T
S
S
T
T
N
N
P
P
330
|
I
I
A
A
S
S
I
I
F
F
A
A
W
W
T
T
R
R
G
G
340
|
L
L
A
A
H
H
R
R
A
A
K
K
L
L
D
D
N
N
N
N
350
|
K
K
E
E
L
L
A
A
F
F
F
F
A
A
N
N
A
A
L
L
360
|
E
E
E
E
V
V
S
S
I
I
E
E
T
T
I
I
E
E
A
A
370
|
G
G
F
F
M
M
T
T
K
K
D
D
L
L
A
A
A
A
C
C
380
|
I
I
K
K
G
G
L
L
P
P
N
N
V
V
Q
Q
R
R
S
S
390
|
D
D
Y
Y
L
L
N
N
T
T
F
F
E
E
F
F
M
M
D
D
400
|
K
K
L
L
G
G
E
E
N
N
L
L
K
K
I
I
K
K
L
L
410
|
A
A
Q
Q
A
A
K
K
L
L
S
S
L
L
E
E
H
H
H
H
420
|
H
H
H
H
H
H
H
H
H
H
H
H
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
In Vitro Model Brain N.A.
Experiment for
Molecule Alteration		 Multiplex array; Standard ELISA assay
Experiment for
Drug Resistance		 Pharmacokinetics analysis
References
Ref 1 Identification of different ALK mutations in a pair of neuroblastoma cell lines established at diagnosis and relapse. Oncotarget. 2016 Dec 27;7(52):87301-87311. doi: 10.18632/oncotarget.13541.
Ref 2 5-azacytidine reduces methylation, promotes differentiation and induces tumor regression in a patient-derived IDH1 mutant glioma xenograftOncotarget. 2013 Oct;4(10):1737-47. doi: 10.18632/oncotarget.1408.
Ref 3 Correlation between IDH1 gene mutation status and survival of patients treated for recurrent gliomaAnticancer Res. 2011 Dec;31(12):4457-63.
Ref 4 The neuroblastoma-associated F1174L ALK mutation causes resistance to an ALK kinase inhibitor in ALK-translocated cancers. Cancer Res. 2010 Dec 15;70(24):10038-43. doi: 10.1158/0008-5472.CAN-10-2956. Epub 2010 Oct 28.
Ref 5 Concurrent BRAF/MEK Inhibitors in BRAF V600-Mutant High-Grade Primary Brain TumorsJ Natl Compr Canc Netw. 2018 Apr;16(4):343-347. doi: 10.6004/jnccn.2017.7052.
Ref 6 2-Hydroxyglutarate produced by neomorphic IDH mutations suppresses homologous recombination and induces PARP inhibitor sensitivitySci Transl Med. 2017 Feb 1;9(375):eaal2463. doi: 10.1126/scitranslmed.aal2463.
Ref 7 Durable Control of Metastatic AKT1-Mutant WHO Grade 1 Meningothelial Meningioma by the AKT Inhibitor, AZD5363J Natl Cancer Inst. 2017 Mar 1;109(3):1-4. doi: 10.1093/jnci/djw320.
Ref 8 AG-221, a First-in-Class Therapy Targeting Acute Myeloid Leukemia Harboring Oncogenic IDH2 MutationsCancer Discov. 2017 May;7(5):478-493. doi: 10.1158/2159-8290.CD-16-1034. Epub 2017 Feb 13.
Ref 9 Selumetinib in paediatric patients with BRAF-aberrant or neurofibromatosis type 1-associated recurrent, refractory, or progressive low-grade glioma: a multicentre, phase 2 trialLancet Oncol. 2019 Jul;20(7):1011-1022. doi: 10.1016/S1470-2045(19)30277-3. Epub 2019 May 28.
Ref 10 First-in-Class ERK1/2 Inhibitor Ulixertinib (BVD-523) in Patients with MAPK Mutant Advanced Solid Tumors: Results of a Phase I Dose-Escalation and Expansion StudyCancer Discov. 2018 Feb;8(2):184-195. doi: 10.1158/2159-8290.CD-17-1119. Epub 2017 Dec 15.
Ref 11 Targeting a Plk1-Controlled Polarity Checkpoint in Therapy-Resistant Glioblastoma-Propagating CellsCancer Res. 2015 Dec 15;75(24):5355-66. doi: 10.1158/0008-5472.CAN-14-3689. Epub 2015 Nov 16.
Ref 12 Targeted therapy for BRAFV600E malignant astrocytomaClin Cancer Res. 2011 Dec 15;17(24):7595-604. doi: 10.1158/1078-0432.CCR-11-1456. Epub 2011 Oct 28.
Ref 13 An inhibitor of mutant IDH1 delays growth and promotes differentiation of glioma cellsScience. 2013 May 3;340(6132):626-30. doi: 10.1126/science.1236062. Epub 2013 Apr 4.
Ref 14 Inhibition of glutaminase preferentially slows growth of glioma cells with mutant IDH1Cancer Res. 2010 Nov 15;70(22):8981-7. doi: 10.1158/0008-5472.CAN-10-1666. Epub 2010 Nov 2.
Ref 15 Targeting the mTOR Complex by Everolimus in NRAS Mutant NeuroblastomaPLoS One. 2016 Jan 28;11(1):e0147682. doi: 10.1371/journal.pone.0147682. eCollection 2016.
Ref 16 BRAF Status in Personalizing Treatment Approaches for Pediatric GliomasClin Cancer Res. 2016 Nov 1;22(21):5312-5321. doi: 10.1158/1078-0432.CCR-15-1101. Epub 2016 May 23.
Ref 17 Anti-tumor effect of a novel PI3-kinase inhibitor, SF1126, in (12) V-Ha-Ras transgenic mouse glioma modelCancer Cell Int. 2014 Nov 12;14(1):105. doi: 10.1186/s12935-014-0105-9. eCollection 2014.
Ref 18 Novel ALK inhibitor AZD3463 inhibits neuroblastoma growth by overcoming crizotinib resistance and inducing apoptosisSci Rep. 2016 Jan 20;6:19423. doi: 10.1038/srep19423.
Ref 19 CEP-28122, a highly potent and selective orally active inhibitor of anaplastic lymphoma kinase with antitumor activity in experimental models of human cancersMol Cancer Ther. 2012 Mar;11(3):670-9. doi: 10.1158/1535-7163.MCT-11-0776. Epub 2011 Dec 27.
Ref 20 Regression of BRAF (V600E) mutant adult glioblastoma after primary combined BRAF-MEK inhibitor targeted therapy: a report of two casesOncotarget. 2019 Jun 4;10(38):3818-3826. eCollection 2019 Jun 4.
Ref 21 A Multicenter, Phase II, Randomized, Noncomparative Clinical Trial of Radiation and Temozolomide with or without Vandetanib in Newly Diagnosed Glioblastoma PatientsClin Cancer Res. 2015 Aug 15;21(16):3610-8. doi: 10.1158/1078-0432.CCR-14-3220. Epub 2015 Apr 24.

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