Disease Information

General Information of the Disease (ID: DIS00060)
Name
Acute lymphocytic leukemia
ICD
ICD-11: 2B33
Resistance Map
Type(s) of Resistant Mechanism of This Disease with Structure Alteration
  ADTT: Aberration of the Drug's Therapeutic Target
  DISM: Drug Inactivation by Structure Modification
  UAPP: Unusual Activation of Pro-survival Pathway
Drug Resistance Data Categorized by Drug
Approved Drug(s)
5 drug(s) in total
Click to Show/Hide the Full List of Drugs
Dasatinib
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: Tyrosine-protein kinase ABL1 (ABL1) [1], [2]
Resistant Disease Acute lymphocytic leukemia [ICD-11: 2B33.0]
Resistant Drug Dasatinib
 Drug Info 
Molecule Alteration Missense mutation
p.T315I
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 2.89  Å
PDB: 4XEY
Mutant Type Structure Method: X-ray diffraction Resolution: 2.17  Å
PDB: 5MO4
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.69
TM score: 0.88225
Amino acid change:
T315I
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
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40
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G
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A
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M
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D
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50
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R
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P
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A
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D
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F
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E
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P
-
Q
60
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-
G
-
L
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S
-
E
-
A
-
A
-
R
-
W
-
N
-
S
70
|
-
K
-
E
-
N
-
L
-
L
-
A
-
G
-
P
-
S
-
E
80
|
-
N
-
D
-
P
-
N
-
L
-
F
-
V
-
A
-
L
-
Y
90
|
-
D
-
F
-
V
-
A
-
S
-
G
-
D
-
N
-
T
-
L
100
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-
S
-
I
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T
-
K
-
G
-
E
-
K
-
L
-
R
-
V
110
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-
L
-
G
-
Y
-
N
-
H
-
N
-
G
-
E
-
W
-
C
120
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-
E
-
A
-
Q
-
T
-
K
-
N
-
G
-
Q
-
G
-
W
130
|
-
V
-
P
-
S
-
N
-
Y
M
I
A
T
S
P
V
V
N
N
140
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S
S
L
L
E
E
K
K
H
H
S
S
W
W
Y
Y
H
H
G
G
150
|
P
P
V
V
S
S
R
R
N
N
A
A
A
A
E
E
Y
Y
L
L
160
|
L
L
S
S
S
S
G
G
I
I
N
N
G
G
S
S
F
F
L
L
170
|
V
V
R
R
E
E
S
S
E
E
S
S
S
S
P
P
G
G
Q
Q
180
|
R
R
S
S
I
I
S
S
L
L
R
R
Y
Y
E
E
G
G
R
R
190
|
V
V
Y
Y
H
H
Y
Y
R
R
I
I
N
N
T
T
A
A
S
S
200
|
D
D
G
G
K
K
L
L
Y
Y
V
V
S
S
S
S
E
E
S
S
210
|
R
R
F
F
N
N
T
T
L
L
A
A
E
E
L
L
V
V
H
H
220
|
H
H
H
H
S
S
T
T
V
V
A
A
D
D
G
G
L
L
I
I
230
|
T
T
T
T
L
L
H
H
Y
Y
P
P
A
A
P
P
K
K
R
R
240
|
N
N
K
K
P
P
T
T
V
V
Y
Y
G
G
V
V
S
S
P
P
250
|
N
N
Y
Y
D
D
K
K
W
W
E
E
M
M
E
E
R
R
T
T
260
|
D
D
I
I
T
T
M
M
K
K
H
H
K
K
L
L
G
G
G
G
270
|
G
G
Q
Q
Y
Y
G
G
E
E
V
V
Y
Y
E
E
G
G
V
V
280
|
W
W
K
K
K
K
Y
Y
S
S
L
L
T
T
V
V
A
A
V
V
290
|
K
K
T
T
L
L
K
K
E
E
D
D
T
T
M
M
E
E
V
V
300
|
E
E
E
E
F
F
L
L
K
K
E
E
A
A
A
A
V
V
M
M
310
|
K
K
E
E
I
I
K
K
H
H
P
P
N
N
L
L
V
V
Q
Q
320
|
L
L
L
L
G
G
V
V
C
C
T
T
R
R
E
E
P
P
P
P
330
|
F
F
Y
Y
I
I
I
I
T
I
E
E
F
F
M
M
T
T
Y
Y
340
|
G
G
N
N
L
L
L
L
D
D
Y
Y
L
L
R
R
E
E
C
C
350
|
N
N
R
R
Q
Q
E
E
V
V
N
N
A
A
V
V
V
V
L
L
360
|
L
L
Y
Y
M
M
A
A
T
T
Q
Q
I
I
S
S
S
S
A
A
370
|
M
M
E
E
Y
Y
L
L
E
E
K
K
K
K
N
N
F
F
I
I
380
|
H
H
R
R
D
N
L
L
A
A
A
A
R
R
N
N
C
C
L
L
390
|
V
V
G
G
E
E
N
N
H
H
L
L
V
V
K
K
V
V
A
A
400
|
D
D
F
F
G
G
L
L
S
S
R
R
L
L
M
M
T
T
G
G
410
|
D
D
T
T
Y
Y
T
T
A
A
H
H
A
A
G
G
A
A
K
K
420
|
F
F
P
P
I
I
K
K
W
W
T
T
A
A
P
P
E
E
S
S
430
|
L
L
A
A
Y
Y
N
N
K
K
F
F
S
S
I
I
K
K
S
S
440
|
D
D
V
V
W
W
A
A
F
F
G
G
V
V
L
L
L
L
W
W
450
|
E
E
I
I
A
A
T
T
Y
Y
G
G
M
M
S
S
P
P
Y
Y
460
|
P
P
G
G
I
I
D
D
L
L
S
S
Q
Q
V
V
Y
Y
E
E
470
|
L
L
L
L
E
E
K
K
D
D
Y
Y
R
R
M
M
E
E
R
R
480
|
P
P
E
E
G
G
C
C
P
P
E
E
K
K
V
V
Y
Y
E
E
490
|
L
L
M
M
R
R
A
A
C
C
W
W
Q
Q
W
W
N
N
P
P
500
|
S
S
D
D
R
R
P
P
S
S
F
F
A
A
E
E
I
I
H
H
510
|
Q
Q
A
A
F
F
E
E
T
T
M
M
F
F
Q
Q
E
E
S
S
520
|
S
S
I
I
S
S
D
D
E
E
V
V
E
E
K
K
E
E
L
L
530
|
G
G
K
K
Q
Q
G
G
V
V
L
-
E
-
H
-
H
-
H
-
540
|
H
-
H
-
H
-
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Drug Resistance		 Flow cytometry assay; Analysis of disease free and overall survival assay
Mechanism Description Mutations were frequently detected at relapse. Among 17 patients analyzed, a T315I mutation was detected in 12, E255k in 1, and no BCR-ABL mutations in 4 (25886620). Thirteen relapsed patients had mutational analysis and 7 had ABL mutations (4 T315I, 1 F359V, and 2 V299L).
Imatinib
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: Tyrosine-protein kinase ABL1 (ABL1) [3], [4]
Resistant Disease Acute lymphocytic leukemia [ICD-11: 2B33.0]
Resistant Drug Imatinib
 Drug Info 
Molecule Alteration Missense mutation
p.H396P
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 2.20  Å
PDB: 4WA9
Mutant Type Structure Method: X-ray diffraction Resolution: 2.00  Å
PDB: 2G2H
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.35
TM score: 0.96269
Amino acid change:
H396P
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
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G
-
S
-
S
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230
|
P
-
N
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Y
-
D
-
K
-
W
-
E
-
M
-
E
-
R
-
240
|
T
-
D
-
I
-
T
-
M
-
K
G
H
H
K
M
L
S
G
P
250
|
G
N
G
Y
Q
D
Y
K
G
W
E
E
V
M
Y
E
E
R
G
T
260
|
V
D
W
I
K
T
K
M
Y
K
S
H
L
K
T
L
V
G
A
G
270
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V
G
K
Q
T
Y
L
G
K
E
E
V
D
Y
T
E
M
G
E
V
280
|
V
W
E
K
E
K
F
Y
L
S
K
L
E
T
A
V
A
A
V
V
290
|
M
K
K
T
E
L
I
K
K
E
H
D
P
T
N
M
L
E
V
V
300
|
Q
E
L
E
L
F
G
L
V
K
C
E
T
A
R
A
E
V
P
M
310
|
P
K
F
E
Y
I
I
K
I
H
T
P
E
N
F
L
M
V
T
Q
320
|
Y
L
G
L
N
G
L
V
L
C
D
T
Y
R
L
E
R
P
E
P
330
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C
F
N
Y
R
I
Q
I
E
T
V
E
N
F
A
M
V
T
V
Y
340
|
L
G
L
N
Y
L
M
L
A
D
T
Y
Q
L
I
R
S
E
S
C
350
|
A
N
M
R
E
Q
Y
E
L
V
E
N
K
A
K
V
N
V
F
L
360
|
I
L
H
Y
R
M
D
A
L
T
A
Q
A
I
R
S
N
S
C
A
370
|
L
M
V
E
G
Y
E
L
N
E
H
K
L
K
V
N
K
F
V
I
380
|
A
H
D
R
F
D
G
L
L
A
S
A
R
R
L
N
M
C
T
L
390
|
G
V
D
G
T
E
Y
N
T
H
A
L
H
V
A
K
G
V
A
A
400
|
K
D
F
F
P
G
I
L
K
S
W
R
T
L
A
M
P
T
E
G
410
|
S
D
L
T
A
Y
Y
T
N
A
K
P
F
A
S
G
I
A
K
K
420
|
S
F
D
P
V
I
W
K
A
W
F
T
G
A
V
P
L
E
L
S
430
|
W
L
E
A
I
Y
A
N
T
K
Y
F
G
S
M
I
S
K
P
S
440
|
Y
D
P
V
G
W
I
A
D
F
L
G
S
V
Q
L
V
L
Y
W
450
|
E
E
L
I
L
A
E
T
K
Y
D
G
Y
M
R
S
M
P
E
Y
460
|
R
P
P
G
E
I
G
D
C
L
P
S
E
Q
K
V
V
Y
Y
E
470
|
E
L
L
L
M
E
R
K
A
D
C
Y
W
R
Q
M
W
E
N
R
480
|
P
P
S
E
D
G
R
C
P
P
S
E
F
K
A
V
E
Y
I
E
490
|
H
L
Q
M
A
R
F
A
E
C
T
W
M
Q
F
W
Q
N
E
P
500
|
S
S
S
D
I
R
S
P
D
S
E
F
V
A
E
E
K
I
E
H
510
|
L
Q
G
A
K
F
-
E
-
T
-
M
-
F
-
Q
-
E
-
S
520
|
-
S
-
I
-
S
-
D
-
E
-
V
-
E
-
K
-
E
-
L
530
|
-
G
-
K
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 CR-Abl sequencing assay
Experiment for
Drug Resistance		 Event-free survival assay
Mechanism Description M244V and H396 mutations have been shown to be more resistant to imatinib but both have been shown to be sensitive to second generation TkI's such as nilotinib and dasatinib.
Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [3]
Resistant Disease Acute lymphocytic leukemia [ICD-11: 2B33.0]
Resistant Drug Imatinib
 Drug Info 
Molecule Alteration Missense mutation
p.T315I
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 2.89  Å
PDB: 4XEY
Mutant Type Structure Method: X-ray diffraction Resolution: 2.17  Å
PDB: 5MO4
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.69
TM score: 0.88225
Amino acid change:
T315I
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
40
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-
G
-
A
-
M
-
D
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P
-
S
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E
-
A
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50
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A
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F
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E
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P
-
Q
60
|
-
G
-
L
-
S
-
E
-
A
-
A
-
R
-
W
-
N
-
S
70
|
-
K
-
E
-
N
-
L
-
L
-
A
-
G
-
P
-
S
-
E
80
|
-
N
-
D
-
P
-
N
-
L
-
F
-
V
-
A
-
L
-
Y
90
|
-
D
-
F
-
V
-
A
-
S
-
G
-
D
-
N
-
T
-
L
100
|
-
S
-
I
-
T
-
K
-
G
-
E
-
K
-
L
-
R
-
V
110
|
-
L
-
G
-
Y
-
N
-
H
-
N
-
G
-
E
-
W
-
C
120
|
-
E
-
A
-
Q
-
T
-
K
-
N
-
G
-
Q
-
G
-
W
130
|
-
V
-
P
-
S
-
N
-
Y
M
I
A
T
S
P
V
V
N
N
140
|
S
S
L
L
E
E
K
K
H
H
S
S
W
W
Y
Y
H
H
G
G
150
|
P
P
V
V
S
S
R
R
N
N
A
A
A
A
E
E
Y
Y
L
L
160
|
L
L
S
S
S
S
G
G
I
I
N
N
G
G
S
S
F
F
L
L
170
|
V
V
R
R
E
E
S
S
E
E
S
S
S
S
P
P
G
G
Q
Q
180
|
R
R
S
S
I
I
S
S
L
L
R
R
Y
Y
E
E
G
G
R
R
190
|
V
V
Y
Y
H
H
Y
Y
R
R
I
I
N
N
T
T
A
A
S
S
200
|
D
D
G
G
K
K
L
L
Y
Y
V
V
S
S
S
S
E
E
S
S
210
|
R
R
F
F
N
N
T
T
L
L
A
A
E
E
L
L
V
V
H
H
220
|
H
H
H
H
S
S
T
T
V
V
A
A
D
D
G
G
L
L
I
I
230
|
T
T
T
T
L
L
H
H
Y
Y
P
P
A
A
P
P
K
K
R
R
240
|
N
N
K
K
P
P
T
T
V
V
Y
Y
G
G
V
V
S
S
P
P
250
|
N
N
Y
Y
D
D
K
K
W
W
E
E
M
M
E
E
R
R
T
T
260
|
D
D
I
I
T
T
M
M
K
K
H
H
K
K
L
L
G
G
G
G
270
|
G
G
Q
Q
Y
Y
G
G
E
E
V
V
Y
Y
E
E
G
G
V
V
280
|
W
W
K
K
K
K
Y
Y
S
S
L
L
T
T
V
V
A
A
V
V
290
|
K
K
T
T
L
L
K
K
E
E
D
D
T
T
M
M
E
E
V
V
300
|
E
E
E
E
F
F
L
L
K
K
E
E
A
A
A
A
V
V
M
M
310
|
K
K
E
E
I
I
K
K
H
H
P
P
N
N
L
L
V
V
Q
Q
320
|
L
L
L
L
G
G
V
V
C
C
T
T
R
R
E
E
P
P
P
P
330
|
F
F
Y
Y
I
I
I
I
T
I
E
E
F
F
M
M
T
T
Y
Y
340
|
G
G
N
N
L
L
L
L
D
D
Y
Y
L
L
R
R
E
E
C
C
350
|
N
N
R
R
Q
Q
E
E
V
V
N
N
A
A
V
V
V
V
L
L
360
|
L
L
Y
Y
M
M
A
A
T
T
Q
Q
I
I
S
S
S
S
A
A
370
|
M
M
E
E
Y
Y
L
L
E
E
K
K
K
K
N
N
F
F
I
I
380
|
H
H
R
R
D
N
L
L
A
A
A
A
R
R
N
N
C
C
L
L
390
|
V
V
G
G
E
E
N
N
H
H
L
L
V
V
K
K
V
V
A
A
400
|
D
D
F
F
G
G
L
L
S
S
R
R
L
L
M
M
T
T
G
G
410
|
D
D
T
T
Y
Y
T
T
A
A
H
H
A
A
G
G
A
A
K
K
420
|
F
F
P
P
I
I
K
K
W
W
T
T
A
A
P
P
E
E
S
S
430
|
L
L
A
A
Y
Y
N
N
K
K
F
F
S
S
I
I
K
K
S
S
440
|
D
D
V
V
W
W
A
A
F
F
G
G
V
V
L
L
L
L
W
W
450
|
E
E
I
I
A
A
T
T
Y
Y
G
G
M
M
S
S
P
P
Y
Y
460
|
P
P
G
G
I
I
D
D
L
L
S
S
Q
Q
V
V
Y
Y
E
E
470
|
L
L
L
L
E
E
K
K
D
D
Y
Y
R
R
M
M
E
E
R
R
480
|
P
P
E
E
G
G
C
C
P
P
E
E
K
K
V
V
Y
Y
E
E
490
|
L
L
M
M
R
R
A
A
C
C
W
W
Q
Q
W
W
N
N
P
P
500
|
S
S
D
D
R
R
P
P
S
S
F
F
A
A
E
E
I
I
H
H
510
|
Q
Q
A
A
F
F
E
E
T
T
M
M
F
F
Q
Q
E
E
S
S
520
|
S
S
I
I
S
S
D
D
E
E
V
V
E
E
K
K
E
E
L
L
530
|
G
G
K
K
Q
Q
G
G
V
V
L
-
E
-
H
-
H
-
H
-
540
|
H
-
H
-
H
-
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Mechanism Description Different mutations within the kinase domain of BCR-ABL can be responsible for refractoriness of Ph+ leukaemia to STI571. Mutation in the BCR-ABL kinase domain might be a frequent mechanism of STI571 resistance in lymphoid disease. In summary, binding of STI571 to BCR-ABL depends on a number of specific interactions within the ATPbinding site. Our results strongly suggest that a patient could be resistant to STI571 by acquisition of different individual point mutations within the ATP-binding pocket or activation loop of BCR-ABL, even though the number of mutations might be limited. This factor could make it difficult to overcome resistance to STI571 by use of alternative kinase inhibitors.
Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [5]
Resistant Disease Acute lymphocytic leukemia [ICD-11: 2B33.0]
Resistant Drug Imatinib
 Drug Info 
Molecule Alteration Missense mutation
p.G250E
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 2.17  Å
PDB: 5MO4
Mutant Type Structure Method: Solution NMR Resolution: N.A.
PDB: 6XRG
   Download The Information of Sequence       Download The Structure File   
RMSD: 2.4
TM score: 0.79586
Amino acid change:
G250E
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
G
-
60
|
A
-
M
-
D
-
P
-
S
-
E
-
A
-
L
-
Q
-
R
-
70
|
P
-
V
-
A
-
S
-
D
-
F
-
E
-
P
-
Q
-
G
-
80
|
L
-
S
-
E
-
A
-
A
-
R
-
W
-
N
-
S
-
K
-
90
|
E
-
N
-
L
-
L
-
A
-
G
-
P
-
S
-
E
-
N
-
100
|
D
-
P
-
N
-
L
-
F
-
V
-
A
-
L
-
Y
-
D
-
110
|
F
-
V
-
A
-
S
-
G
-
D
-
N
-
T
-
L
-
S
-
120
|
I
-
T
-
K
-
G
-
E
-
K
-
L
-
R
-
V
-
L
-
130
|
G
-
Y
-
N
-
H
-
N
-
G
-
E
-
W
-
C
-
E
-
140
|
A
-
Q
-
T
-
K
-
N
-
G
-
Q
-
G
-
W
-
V
-
150
|
P
-
S
-
N
-
Y
-
I
-
T
-
P
-
V
-
N
-
S
-
160
|
L
-
E
-
K
-
H
-
S
-
W
-
Y
-
H
-
G
-
P
-
170
|
V
-
S
-
R
-
N
-
A
-
A
-
E
-
Y
-
L
-
L
-
180
|
S
-
S
-
G
-
I
-
N
-
G
-
S
-
F
-
L
-
V
-
190
|
R
-
E
-
S
-
E
-
S
-
S
-
P
-
G
-
Q
-
R
-
200
|
S
-
I
-
S
-
L
-
R
-
Y
-
E
-
G
-
R
-
V
-
210
|
Y
-
H
-
Y
-
R
-
I
-
N
-
T
-
A
-
S
-
D
-
220
|
G
-
K
-
L
-
Y
-
V
-
S
-
S
-
E
-
S
-
R
-
230
|
F
-
N
-
T
-
L
-
A
-
E
-
L
-
V
-
H
-
H
-
240
|
H
-
S
-
T
-
V
-
A
-
D
-
G
-
L
-
I
-
T
-
250
|
T
-
L
-
H
-
Y
-
P
-
A
-
P
-
K
-
R
-
N
-
260
|
K
-
P
-
T
-
V
-
Y
-
G
-
V
-
S
S
P
P
N
N
270
|
Y
Y
D
D
K
K
W
W
E
E
M
M
E
E
R
R
T
T
D
D
280
|
I
I
T
T
M
M
K
K
H
H
K
K
L
L
G
G
G
E
G
G
290
|
Q
Q
Y
Y
G
G
E
E
V
V
Y
Y
E
E
G
G
V
V
W
W
300
|
K
K
K
K
Y
Y
S
S
L
L
T
T
V
V
A
A
V
V
K
K
310
|
T
T
L
L
K
K
E
E
D
D
T
T
M
M
E
E
V
V
E
E
320
|
E
E
F
F
L
L
K
K
E
E
A
A
A
A
V
V
M
L
K
K
330
|
E
E
I
I
K
K
H
H
P
P
N
N
L
L
V
V
Q
Q
L
L
340
|
L
L
G
G
V
V
C
C
T
T
R
R
E
E
P
P
P
P
F
F
350
|
Y
Y
I
I
I
I
I
T
E
E
F
F
M
M
T
T
Y
Y
G
G
360
|
N
N
L
L
L
L
D
D
Y
Y
L
L
R
R
E
E
C
C
N
N
370
|
R
R
Q
Q
E
E
V
V
N
N
A
A
V
V
V
V
L
L
L
L
380
|
Y
Y
M
M
A
A
T
T
Q
Q
I
I
S
S
S
S
A
A
M
M
390
|
E
E
Y
Y
L
L
E
E
K
K
K
K
N
N
F
F
I
I
H
H
400
|
R
R
N
D
L
L
A
A
A
A
R
R
N
N
C
C
L
L
V
V
410
|
G
G
E
E
N
N
H
H
L
L
V
V
K
K
V
V
A
A
D
D
420
|
F
F
G
G
L
L
S
S
R
R
L
L
M
M
T
Y
G
G
D
D
430
|
T
T
Y
Y
T
T
A
A
H
H
A
A
G
G
A
A
K
K
F
F
440
|
P
P
I
I
K
K
W
W
T
T
A
A
P
P
E
E
S
S
L
L
450
|
A
A
Y
Y
N
N
K
K
F
F
S
S
I
I
K
K
S
S
D
D
460
|
V
V
W
W
A
A
F
F
G
G
V
V
L
L
L
L
W
W
E
E
470
|
I
I
A
A
T
T
Y
Y
G
G
M
M
S
S
P
P
Y
Y
P
P
480
|
G
G
I
I
D
D
L
L
S
S
Q
Q
V
V
Y
Y
E
E
L
L
490
|
L
L
E
E
K
K
D
D
Y
Y
R
R
M
M
E
E
R
R
P
P
500
|
E
E
G
G
C
C
P
P
E
E
K
K
V
V
Y
Y
E
E
L
L
510
|
M
M
R
R
A
A
C
C
W
W
Q
Q
W
W
N
N
P
P
S
S
520
|
D
D
R
R
P
P
S
S
F
F
A
A
E
E
I
I
H
H
Q
Q
530
|
A
A
F
F
E
E
T
T
M
M
F
F
Q
Q
E
E
S
S
S
S
540
|
I
I
S
S
D
D
E
E
V
V
E
E
K
K
E
E
L
L
G
G
550
|
K
K
Q
Q
G
G
V
V
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 PCR-Invader assay; Direct sequencing assay
Experiment for
Drug Resistance		 Progression-free survival assay; Overall survival assay
Mechanism Description The PCR-Invader assay used in this study is an appropriate tool for the screening of mutations during TkI therapy. High Sokal score is only predictive factor for emergence of mutation in CML-CP. P-loop mutations were associated with poor PFS in CML-CP.
Mercaptopurine
Click to Show/Hide
Drug Resistance Data Categorized by Their Corresponding Mechanisms
  Drug Inactivation by Structure Modification (DISM) Click to Show/Hide
Key Molecule: Cytosolic purine 5'-nucleotidase (NT5C2) [6]
Resistant Disease Acute lymphocytic leukemia [ICD-11: 2B33.0]
Resistant Drug Mercaptopurine
 Drug Info 
Molecule Alteration Missense mutation
p.R367Q
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 2.30  Å
PDB: 6FXH
Mutant Type Structure Method: X-ray diffraction Resolution: 2.50  Å
PDB: 6DDK
   Download The Information of Sequence       Download The Structure File   
RMSD: 2.64
TM score: 0.87692
Amino acid change:
R367Q
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
-
G
-
S
-
S
-
H
-
H
-
H
-
H
-10
|
-
H
-
H
-
S
-
S
-
G
-
L
-
V
-
P
-
R
-
G
0
|
-
S
M
M
S
S
T
T
S
S
W
W
S
S
D
D
R
R
L
L
10
|
Q
Q
N
N
A
A
A
A
D
D
M
M
P
P
A
A
N
N
M
M
20
|
D
D
K
K
H
H
A
A
L
L
K
K
K
K
Y
Y
R
R
R
R
30
|
E
E
A
A
Y
Y
H
H
R
R
V
V
F
F
V
V
N
N
R
R
40
|
S
S
L
L
A
A
M
M
E
E
K
K
I
I
K
K
C
C
F
F
50
|
G
G
F
F
D
N
M
M
D
D
Y
Y
T
T
L
L
A
A
V
V
60
|
Y
Y
K
K
S
S
P
P
E
E
Y
Y
E
E
S
S
L
L
G
G
70
|
F
F
E
E
L
L
T
T
V
V
E
E
R
R
L
L
V
V
S
S
80
|
I
I
G
G
Y
Y
P
P
Q
Q
E
E
L
L
L
L
S
S
F
F
90
|
A
A
Y
Y
D
D
S
S
T
T
F
F
P
P
T
T
R
R
G
G
100
|
L
L
V
V
F
F
D
D
T
T
L
L
Y
Y
G
G
N
N
L
L
110
|
L
L
K
K
V
V
D
D
A
A
Y
Y
G
G
N
N
L
L
L
L
120
|
V
V
C
C
A
A
H
H
G
G
F
F
N
N
F
F
I
I
R
R
130
|
G
G
P
P
E
E
T
T
R
R
E
E
Q
Q
Y
Y
P
P
N
N
140
|
K
K
F
F
I
I
Q
Q
R
R
D
D
D
D
T
T
E
E
R
R
150
|
F
F
Y
Y
I
I
L
L
N
N
T
T
L
L
F
F
N
N
L
L
160
|
P
P
E
E
T
T
Y
Y
L
L
L
L
A
A
C
C
L
L
V
V
170
|
D
D
F
F
F
F
T
T
N
N
C
C
P
P
R
R
Y
Y
T
T
180
|
S
S
C
C
E
E
T
T
G
G
F
F
K
K
D
D
G
G
D
D
190
|
L
L
F
F
M
M
S
S
Y
Y
R
R
S
S
M
M
F
F
Q
Q
200
|
D
D
V
V
R
R
D
D
A
A
V
V
D
D
W
W
V
V
H
H
210
|
Y
Y
K
K
G
G
S
S
L
L
K
K
E
E
K
K
T
T
V
V
220
|
E
E
N
N
L
L
E
E
K
K
Y
Y
V
V
V
V
K
K
D
D
230
|
G
G
K
K
L
L
P
P
L
L
L
L
L
L
S
S
R
R
M
M
240
|
K
K
E
E
V
V
G
G
K
K
V
V
F
F
L
L
A
A
T
T
250
|
N
N
S
S
D
D
Y
Y
K
K
Y
Y
T
T
D
D
K
K
I
I
260
|
M
M
T
T
Y
Y
L
L
F
F
D
D
F
F
P
P
H
H
G
G
270
|
P
P
K
K
P
P
G
G
S
S
S
S
H
H
R
R
P
P
W
W
280
|
Q
Q
S
S
Y
Y
F
F
D
D
L
L
I
I
L
L
V
V
D
D
290
|
A
A
R
R
K
K
P
P
L
L
F
F
F
F
G
G
E
E
G
G
300
|
T
T
V
V
L
L
R
R
Q
Q
V
V
D
D
T
T
K
K
T
T
310
|
G
G
K
K
L
L
K
K
I
I
G
G
T
T
Y
Y
T
T
G
G
320
|
P
P
L
L
Q
Q
H
H
G
G
I
I
V
V
Y
Y
S
S
G
G
330
|
G
G
S
S
S
S
D
D
T
T
I
I
C
C
D
D
L
L
L
L
340
|
G
G
A
A
K
K
G
G
K
K
D
D
I
I
L
L
Y
Y
I
I
350
|
G
G
D
D
H
H
I
I
F
F
G
G
D
D
I
I
L
L
K
K
360
|
S
S
K
K
K
K
R
R
Q
Q
G
G
W
W
R
Q
T
T
F
F
370
|
L
L
V
V
I
I
P
P
E
E
L
L
A
A
Q
Q
E
E
L
L
380
|
H
H
V
V
W
W
T
T
D
D
K
K
S
S
S
S
L
L
F
F
390
|
E
E
E
E
L
L
Q
Q
S
S
L
L
D
D
I
I
F
F
L
L
400
|
A
A
E
E
L
L
Y
Y
K
K
H
H
L
L
D
D
S
S
S
S
410
|
S
S
N
N
E
E
R
R
P
P
D
D
I
I
S
S
S
S
I
I
420
|
Q
Q
R
R
R
R
I
I
K
K
K
K
V
V
T
T
H
H
D
D
430
|
M
M
D
D
M
M
C
C
Y
Y
G
G
M
M
M
M
G
G
S
S
440
|
L
L
F
F
R
R
S
S
G
G
S
S
R
R
Q
Q
T
T
L
L
450
|
F
F
A
A
S
S
Q
Q
V
V
M
M
R
R
Y
Y
A
A
D
D
460
|
L
L
Y
Y
A
A
A
A
S
S
F
F
I
I
N
N
L
L
L
L
470
|
Y
Y
Y
Y
P
P
F
F
S
S
Y
Y
L
L
F
F
R
R
A
A
480
|
A
A
H
H
V
V
L
L
M
M
P
P
H
H
E
E
S
S
T
T
490
|
V
V
E
E
H
H
T
T
H
H
V
V
D
D
I
I
N
N
E
E
500
|
M
M
E
E
S
S
P
P
L
L
A
A
T
T
R
R
N
N
R
R
510
|
T
T
S
S
V
V
D
D
F
F
K
K
D
D
T
T
D
D
Y
Y
520
|
K
K
R
R
H
H
Q
Q
L
L
T
T
R
R
S
S
I
I
S
S
530
|
E
E
I
I
K
K
P
P
P
P
N
N
L
L
F
F
P
P
L
L
540
|
A
A
P
P
Q
Q
E
E
I
I
T
T
H
H
C
C
H
H
D
D
550
|
E
E
D
D
D
D
D
D
E
E
E
E
E
E
E
E
E
E
E
E
560
|
E
E
E
E
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
Experiment for
Molecule Alteration		 Exome sequencing assay
Experiment for
Drug Resistance		 Conality analyses assay
Mechanism Description These two NT5C2 mutations (R367Q, D407V) occur as recurrent mutational hotspots in relapse-ALL and they have been functionally validated. These mutations increase the NT5C2 inosine-5-monophosphate-nucleotidase activity; and therefore lead to resistance to one of the chemotherapeutic drugs, 6-mercaptopurine.
Methotrexate
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: GTPase KRas (KRAS) [7]
Resistant Disease Acute lymphocytic leukemia [ICD-11: 2B33.0]
Resistant Drug Methotrexate
 Drug Info 
Molecule Alteration Missense mutation
p.Q61H
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.31  Å
PDB: 6T5V
Mutant Type Structure Method: X-ray diffraction Resolution: 2.20  Å
PDB: 6MNX
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.14
TM score: 0.96411
Amino acid change:
Q61H
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
M
M
T
T
E
E
Y
Y
K
K
L
L
V
V
V
V
V
V
10
|
G
G
A
A
C
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
S
C
L
L
L
L
D
D
I
I
L
L
D
D
T
T
A
A
60
|
G
G
Q
H
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
|
L
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
C
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
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
In Vivo Model Mouse model Mus musculus
Experiment for
Molecule Alteration		 Whole-exome sequencing assay; Whole-genome sequencing assay
Experiment for
Drug Resistance		 Flow cytometric analysis assay; MTT assay
Mechanism Description Notably, drug response a.lyses in isogenic kras wild-type and kras G12D cells showed increased resistance to methotrexate (P < 0.001) upon oncogenic kras activation.
Key Molecule: GTPase KRas (KRAS) [7]
Resistant Disease Acute lymphocytic leukemia [ICD-11: 2B33.0]
Resistant Drug Methotrexate
 Drug Info 
Molecule Alteration Missense mutation
p.G12D
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.40  Å
PDB: 6VJJ
Mutant Type Structure Method: X-ray diffraction Resolution: 2.10  Å
PDB: 8JHL
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.55
TM score: 0.9318
Amino acid change:
G12D
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
0
|
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
D
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
C
C
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
R
V
V
D
E
D
D
A
A
F
F
Y
Y
T
T
L
L
160
|
V
V
R
R
E
E
I
I
R
R
K
Q
H
Y
K
R
E
L
K
K
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
In Vivo Model Mouse model Mus musculus
Experiment for
Molecule Alteration		 Whole-exome sequencing assay; Whole-genome sequencing assay
Experiment for
Drug Resistance		 Flow cytometric analysis assay; MTT assay
Mechanism Description Notably, drug response a.lyses in isogenic kras wild-type and kras G12D cells showed increased resistance to methotrexate (P < 0.001) upon oncogenic kras activation.
Ponatinib
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: BCR-ABL1 e8a2 variant (BCR-ABL1) [8]
Resistant Disease Relapsed acute lymphocytic leukemia [ICD-11: 2B33.5]
Resistant Drug Ponatinib
 Drug Info 
Molecule Alteration Missense mutation
p.T315I
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 2.89  Å
PDB: 4XEY
Mutant Type Structure Method: X-ray diffraction Resolution: 2.17  Å
PDB: 5MO4
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.69
TM score: 0.88225
Amino acid change:
T315I
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
40
|
-
G
-
A
-
M
-
D
-
P
-
S
-
E
-
A
-
L
-
Q
50
|
-
R
-
P
-
V
-
A
-
S
-
D
-
F
-
E
-
P
-
Q
60
|
-
G
-
L
-
S
-
E
-
A
-
A
-
R
-
W
-
N
-
S
70
|
-
K
-
E
-
N
-
L
-
L
-
A
-
G
-
P
-
S
-
E
80
|
-
N
-
D
-
P
-
N
-
L
-
F
-
V
-
A
-
L
-
Y
90
|
-
D
-
F
-
V
-
A
-
S
-
G
-
D
-
N
-
T
-
L
100
|
-
S
-
I
-
T
-
K
-
G
-
E
-
K
-
L
-
R
-
V
110
|
-
L
-
G
-
Y
-
N
-
H
-
N
-
G
-
E
-
W
-
C
120
|
-
E
-
A
-
Q
-
T
-
K
-
N
-
G
-
Q
-
G
-
W
130
|
-
V
-
P
-
S
-
N
-
Y
M
I
A
T
S
P
V
V
N
N
140
|
S
S
L
L
E
E
K
K
H
H
S
S
W
W
Y
Y
H
H
G
G
150
|
P
P
V
V
S
S
R
R
N
N
A
A
A
A
E
E
Y
Y
L
L
160
|
L
L
S
S
S
S
G
G
I
I
N
N
G
G
S
S
F
F
L
L
170
|
V
V
R
R
E
E
S
S
E
E
S
S
S
S
P
P
G
G
Q
Q
180
|
R
R
S
S
I
I
S
S
L
L
R
R
Y
Y
E
E
G
G
R
R
190
|
V
V
Y
Y
H
H
Y
Y
R
R
I
I
N
N
T
T
A
A
S
S
200
|
D
D
G
G
K
K
L
L
Y
Y
V
V
S
S
S
S
E
E
S
S
210
|
R
R
F
F
N
N
T
T
L
L
A
A
E
E
L
L
V
V
H
H
220
|
H
H
H
H
S
S
T
T
V
V
A
A
D
D
G
G
L
L
I
I
230
|
T
T
T
T
L
L
H
H
Y
Y
P
P
A
A
P
P
K
K
R
R
240
|
N
N
K
K
P
P
T
T
V
V
Y
Y
G
G
V
V
S
S
P
P
250
|
N
N
Y
Y
D
D
K
K
W
W
E
E
M
M
E
E
R
R
T
T
260
|
D
D
I
I
T
T
M
M
K
K
H
H
K
K
L
L
G
G
G
G
270
|
G
G
Q
Q
Y
Y
G
G
E
E
V
V
Y
Y
E
E
G
G
V
V
280
|
W
W
K
K
K
K
Y
Y
S
S
L
L
T
T
V
V
A
A
V
V
290
|
K
K
T
T
L
L
K
K
E
E
D
D
T
T
M
M
E
E
V
V
300
|
E
E
E
E
F
F
L
L
K
K
E
E
A
A
A
A
V
V
M
M
310
|
K
K
E
E
I
I
K
K
H
H
P
P
N
N
L
L
V
V
Q
Q
320
|
L
L
L
L
G
G
V
V
C
C
T
T
R
R
E
E
P
P
P
P
330
|
F
F
Y
Y
I
I
I
I
T
I
E
E
F
F
M
M
T
T
Y
Y
340
|
G
G
N
N
L
L
L
L
D
D
Y
Y
L
L
R
R
E
E
C
C
350
|
N
N
R
R
Q
Q
E
E
V
V
N
N
A
A
V
V
V
V
L
L
360
|
L
L
Y
Y
M
M
A
A
T
T
Q
Q
I
I
S
S
S
S
A
A
370
|
M
M
E
E
Y
Y
L
L
E
E
K
K
K
K
N
N
F
F
I
I
380
|
H
H
R
R
D
N
L
L
A
A
A
A
R
R
N
N
C
C
L
L
390
|
V
V
G
G
E
E
N
N
H
H
L
L
V
V
K
K
V
V
A
A
400
|
D
D
F
F
G
G
L
L
S
S
R
R
L
L
M
M
T
T
G
G
410
|
D
D
T
T
Y
Y
T
T
A
A
H
H
A
A
G
G
A
A
K
K
420
|
F
F
P
P
I
I
K
K
W
W
T
T
A
A
P
P
E
E
S
S
430
|
L
L
A
A
Y
Y
N
N
K
K
F
F
S
S
I
I
K
K
S
S
440
|
D
D
V
V
W
W
A
A
F
F
G
G
V
V
L
L
L
L
W
W
450
|
E
E
I
I
A
A
T
T
Y
Y
G
G
M
M
S
S
P
P
Y
Y
460
|
P
P
G
G
I
I
D
D
L
L
S
S
Q
Q
V
V
Y
Y
E
E
470
|
L
L
L
L
E
E
K
K
D
D
Y
Y
R
R
M
M
E
E
R
R
480
|
P
P
E
E
G
G
C
C
P
P
E
E
K
K
V
V
Y
Y
E
E
490
|
L
L
M
M
R
R
A
A
C
C
W
W
Q
Q
W
W
N
N
P
P
500
|
S
S
D
D
R
R
P
P
S
S
F
F
A
A
E
E
I
I
H
H
510
|
Q
Q
A
A
F
F
E
E
T
T
M
M
F
F
Q
Q
E
E
S
S
520
|
S
S
I
I
S
S
D
D
E
E
V
V
E
E
K
K
E
E
L
L
530
|
G
G
K
K
Q
Q
G
G
V
V
L
-
E
-
H
-
H
-
H
-
540
|
H
-
H
-
H
-
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
In Vivo Model A retrospective survey in conducting clinical studies Homo sapiens
Experiment for
Molecule Alteration		 Sanger sequencing assay
Mechanism Description Ponatinib was highly active in heavily pretreated patients with Ph-positive leukemias with resistance to tyrosine kinase inhibitors, including patients with the BCR-ABL T315I mutation, other mutations, or no mutations.
Investigative Drug(s)
3 drug(s) in total
Click to Show/Hide the Full List of Drugs
PD98059
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: Tyrosine-protein phosphatase non-receptor type 11 (PTPN11) [9]
Sensitive Disease Acute lymphocytic leukemia [ICD-11: 2B33.0]
Sensitive Drug PD98059
 Drug Info 
Molecule Alteration Missense mutation
p.E76K (c.226G>A)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.70  Å
PDB: 5EHR
Mutant Type Structure Method: X-ray diffraction Resolution: 2.62  Å
PDB: 6CRF
   Download The Information of Sequence       Download The Structure File   
RMSD: 3.04
TM score: 0.6516
Amino acid change:
E76K
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
0
|
S
G
M
M
T
T
S
S
R
R
R
R
W
W
F
F
H
H
P
P
10
|
N
N
I
I
T
T
G
G
V
V
E
E
A
A
E
E
N
N
L
L
20
|
L
L
L
L
T
T
R
R
G
G
V
V
D
D
G
G
S
S
F
F
30
|
L
L
A
A
R
R
P
P
S
S
K
K
S
S
N
N
P
P
G
G
40
|
D
D
F
F
T
T
L
L
S
S
V
V
R
R
R
R
N
N
G
G
50
|
A
A
V
V
T
T
H
H
I
I
K
K
I
I
Q
Q
N
N
T
T
60
|
G
G
D
D
Y
Y
Y
Y
D
D
L
L
Y
Y
G
G
G
G
E
E
70
|
K
K
F
F
A
A
T
T
L
L
A
A
E
K
L
L
V
V
Q
Q
80
|
Y
Y
Y
Y
M
M
E
E
H
H
H
H
G
G
Q
Q
L
L
K
K
90
|
E
E
K
K
N
N
G
G
D
D
V
V
I
I
E
E
L
L
K
K
100
|
Y
Y
P
P
L
L
N
N
C
C
A
A
D
D
P
P
T
T
S
S
110
|
E
E
R
R
W
W
F
F
H
H
G
G
H
H
L
L
S
S
G
G
120
|
K
K
E
E
A
A
E
E
K
K
L
L
L
L
T
T
E
E
K
K
130
|
G
G
K
K
H
H
G
G
S
S
F
F
L
L
V
V
R
R
E
E
140
|
S
S
Q
Q
S
S
H
H
P
P
G
G
D
D
F
F
V
V
L
L
150
|
S
S
V
V
R
R
T
T
G
G
D
D
D
D
K
K
G
G
E
E
160
|
S
S
N
N
D
D
G
G
K
K
S
S
K
K
V
V
T
T
H
H
170
|
V
V
M
M
I
I
R
R
C
C
Q
Q
E
E
L
L
K
K
Y
Y
180
|
D
D
V
V
G
G
G
G
G
G
E
E
R
R
F
F
D
D
S
S
190
|
L
L
T
T
D
D
L
L
V
V
E
E
H
H
Y
Y
K
K
K
K
200
|
N
N
P
P
M
M
V
V
E
E
T
T
L
L
G
G
T
T
V
V
210
|
L
L
Q
Q
L
L
K
K
Q
Q
P
P
L
L
N
N
T
T
T
T
220
|
R
R
I
I
N
N
A
A
A
A
E
E
I
I
E
E
S
S
R
R
230
|
V
V
R
R
E
E
L
L
S
S
K
K
L
L
A
A
E
E
T
T
240
|
T
T
D
D
K
K
V
V
K
K
Q
Q
G
G
F
F
W
W
E
E
250
|
E
E
F
F
E
E
T
T
L
L
Q
Q
Q
Q
Q
Q
E
E
C
C
260
|
K
K
L
L
L
L
Y
Y
S
S
R
R
K
K
E
E
G
G
Q
Q
270
|
R
R
Q
Q
E
E
N
N
K
K
N
N
K
K
N
N
R
R
Y
Y
280
|
K
K
N
N
I
I
L
L
P
P
F
F
D
D
H
H
T
T
R
R
290
|
V
V
V
V
L
L
H
H
D
D
G
G
D
D
P
P
N
N
E
E
300
|
P
P
V
V
S
S
D
D
Y
Y
I
I
N
N
A
A
N
N
I
I
310
|
I
I
M
M
P
P
E
E
F
F
E
E
T
T
K
K
C
C
N
N
320
|
N
N
S
S
K
K
P
P
K
K
K
K
S
S
Y
Y
I
I
A
A
330
|
T
T
Q
Q
G
G
C
C
L
L
Q
Q
N
N
T
T
V
V
N
N
340
|
D
D
F
F
W
W
R
R
M
M
V
V
F
F
Q
Q
E
E
N
N
350
|
S
S
R
R
V
V
I
I
V
V
M
M
T
T
T
T
K
K
E
E
360
|
V
V
E
E
R
R
G
G
K
K
S
S
K
K
C
C
V
V
K
K
370
|
Y
Y
W
W
P
P
D
D
E
E
Y
Y
A
A
L
L
K
K
E
E
380
|
Y
Y
G
G
V
V
M
M
R
R
V
V
R
R
N
N
V
V
K
K
390
|
E
E
S
S
A
A
A
A
H
H
D
D
Y
Y
T
T
L
L
R
R
400
|
E
E
L
L
K
K
L
L
S
S
K
K
V
V
G
G
Q
Q
G
G
410
|
N
N
T
T
E
E
R
R
T
T
V
V
W
W
Q
Q
Y
Y
H
H
420
|
F
F
R
R
T
T
W
W
P
P
D
D
H
H
G
G
V
V
P
P
430
|
S
S
D
D
P
P
G
G
G
G
V
V
L
L
D
D
F
F
L
L
440
|
E
E
E
E
V
V
H
H
H
H
K
K
Q
Q
E
E
S
S
I
I
450
|
M
M
D
D
A
A
G
G
P
P
V
V
V
V
V
V
H
H
C
C
460
|
S
S
A
A
G
G
I
I
G
G
R
R
T
T
G
G
T
T
F
F
470
|
I
I
V
V
I
I
D
D
I
I
L
L
I
I
D
D
I
I
I
I
480
|
R
R
E
E
K
K
G
G
V
V
D
D
C
C
D
D
I
I
D
D
490
|
V
V
P
P
K
K
T
T
I
I
Q
Q
M
M
V
V
R
R
S
S
500
|
Q
Q
R
R
S
S
G
G
M
M
V
V
Q
Q
T
T
E
E
A
A
510
|
Q
Q
Y
Y
R
R
F
F
I
I
Y
Y
M
M
A
A
V
V
Q
Q
520
|
H
H
Y
Y
I
I
E
E
T
T
L
L
Click to Show/Hide the Structure
Experimental Note Revealed Based on the Cell Line Data
Experiment for
Molecule Alteration		 Immunoblotting analysis
Experiment for
Drug Resistance		 Flow cytometry assay
Mechanism Description The missense mutation p.E76K (c.226G>A) in gene PTPN11 cause the sensitivity of PD98059 by unusual activation of pro-survival pathway
Thiopurine
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: Cytosolic purine 5'-nucleotidase (NT5C2) [7]
Resistant Disease Acute lymphocytic leukemia [ICD-11: 2B33.0]
Resistant Drug Thiopurine
 Drug Info 
Molecule Alteration Missense mutation
p.R238W
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.70  Å
PDB: 5OPP
Mutant Type Structure Method: X-ray diffraction Resolution: 1.84  Å
PDB: 5L4Z
   Download The Information of Sequence       Download The Structure File   
RMSD: 0.41
TM score: 0.99758
Amino acid change:
R238W
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
-
M
-
G
-
S
-
S
-
H
-
H
-
H
-
H
-10
|
-
H
-
H
-
S
-
S
-
G
-
L
-
V
-
P
-
R
-
G
0
|
-
S
-
M
-
S
T
T
S
S
W
W
S
S
D
D
R
R
L
L
10
|
Q
Q
N
N
A
A
A
A
D
D
M
M
P
P
A
A
N
N
M
M
20
|
D
D
K
K
H
H
A
A
L
L
K
K
K
K
Y
Y
R
R
R
R
30
|
E
E
A
A
Y
Y
H
H
R
R
V
V
F
F
V
V
N
N
R
R
40
|
S
S
L
L
A
A
M
M
E
E
K
K
I
I
K
K
C
C
F
F
50
|
G
G
F
F
D
D
M
M
D
D
Y
Y
T
T
L
L
A
A
V
V
60
|
Y
Y
K
K
S
S
P
P
E
E
Y
Y
E
E
S
S
L
L
G
G
70
|
F
F
E
E
L
L
T
T
V
V
E
E
R
R
L
L
V
V
S
S
80
|
I
I
G
G
Y
Y
P
P
Q
Q
E
E
L
L
L
L
S
S
F
F
90
|
A
A
Y
Y
D
D
S
S
T
T
F
F
P
P
T
T
R
R
G
G
100
|
L
L
V
V
F
F
D
D
T
T
L
L
Y
Y
G
G
N
N
L
L
110
|
L
L
K
K
V
V
D
D
A
A
Y
Y
G
G
N
N
L
L
L
L
120
|
V
V
C
C
A
A
H
H
G
G
F
F
N
N
F
F
I
I
R
R
130
|
G
G
P
P
E
E
T
T
R
R
E
E
Q
Q
Y
Y
P
P
N
N
140
|
K
K
F
F
I
I
Q
Q
R
R
D
D
D
D
T
T
E
E
R
R
150
|
F
F
Y
Y
I
I
L
L
N
N
T
T
L
L
F
F
N
N
L
L
160
|
P
P
E
E
T
T
Y
Y
L
L
L
L
A
A
C
C
L
L
V
V
170
|
D
D
F
F
F
F
T
T
N
N
C
C
P
P
R
R
Y
Y
T
T
180
|
S
S
C
C
E
E
T
T
G
G
F
F
K
K
D
D
G
G
D
D
190
|
L
L
F
F
M
M
S
S
Y
Y
R
R
S
S
M
M
F
F
Q
Q
200
|
D
D
V
V
R
R
D
D
A
A
V
V
D
D
W
W
V
V
H
H
210
|
Y
Y
K
K
G
G
S
S
L
L
K
K
E
E
K
K
T
T
V
V
220
|
E
E
N
N
L
L
E
E
K
K
Y
Y
V
V
V
V
K
K
D
D
230
|
G
G
K
K
L
L
P
P
L
L
L
L
L
L
S
S
R
W
M
M
240
|
K
K
E
E
V
V
G
G
K
K
V
V
F
F
L
L
A
A
T
T
250
|
N
N
S
S
D
D
Y
Y
K
K
Y
Y
T
T
D
D
K
K
I
I
260
|
M
M
T
T
Y
Y
L
L
F
F
D
D
F
F
P
P
H
H
G
G
270
|
P
P
K
K
P
P
G
G
S
S
S
S
H
H
R
R
P
P
W
W
280
|
Q
Q
S
S
Y
Y
F
F
D
D
L
L
I
I
L
L
V
V
D
D
290
|
A
A
R
R
K
K
P
P
L
L
F
F
F
F
G
G
E
E
G
G
300
|
T
T
V
V
L
L
R
R
Q
Q
V
V
D
D
T
T
K
K
T
T
310
|
G
G
K
K
L
L
K
K
I
I
G
G
T
T
Y
Y
T
T
G
G
320
|
P
P
L
L
Q
Q
H
H
G
G
I
I
V
V
Y
Y
S
S
G
G
330
|
G
G
S
S
S
S
D
D
T
T
I
I
C
C
D
D
L
L
L
L
340
|
G
G
A
A
K
K
G
G
K
K
D
D
I
I
L
L
Y
Y
I
I
350
|
G
G
D
D
H
H
I
I
F
F
G
G
D
D
I
I
L
L
K
K
360
|
S
S
K
K
K
K
R
R
Q
Q
G
G
W
W
R
R
T
T
F
F
370
|
L
L
V
V
I
I
P
P
E
E
L
L
A
A
Q
Q
E
E
L
L
380
|
H
H
V
V
W
W
T
T
D
D
K
K
S
S
S
S
L
L
F
F
390
|
E
E
E
E
L
L
Q
Q
S
S
L
L
D
D
I
I
F
F
L
L
400
|
A
A
E
E
L
L
Y
Y
K
K
H
H
L
L
D
D
S
S
S
S
410
|
S
S
N
N
E
E
R
R
P
P
D
D
I
I
S
S
S
S
I
I
420
|
Q
Q
R
R
R
R
I
I
K
K
K
K
V
V
T
T
H
H
D
D
430
|
M
M
D
D
M
M
C
C
Y
Y
G
G
M
M
M
M
G
G
S
S
440
|
L
L
F
F
R
R
S
S
G
G
S
S
R
R
Q
Q
T
T
L
L
450
|
F
F
A
A
S
S
Q
Q
V
V
M
M
R
R
Y
Y
A
A
D
D
460
|
L
L
Y
Y
A
A
A
A
S
S
F
F
I
I
N
N
L
L
L
L
470
|
Y
Y
Y
Y
P
P
F
F
S
S
Y
Y
L
L
F
F
R
R
A
A
480
|
A
A
H
H
V
V
L
L
M
M
P
P
H
H
E
E
S
S
-
T
490
|
-
V
-
E
-
H
-
T
-
H
-
V
-
D
-
I
-
N
-
E
500
|
-
M
-
E
-
S
-
P
-
L
-
A
-
T
-
R
-
N
-
R
510
|
-
T
-
S
-
V
-
D
-
F
-
K
-
D
-
T
-
D
-
Y
520
|
-
K
-
R
-
H
-
Q
-
L
-
T
-
R
-
S
-
I
-
S
530
|
-
E
-
I
-
K
-
P
-
P
-
N
-
L
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
Experiment for
Molecule Alteration		 Whole-exome sequencing assay; Whole-genome sequencing assay
Experiment for
Drug Resistance		 Flow cytometric analysis assay; MTT assay
Mechanism Description Finally, genomic profiling of diagnostic and relapsed leukemias has identified relapse-associated mutations in the 5'-nucleotidase, cytosolic II(NT5C2) gene as drivers of resistance to thiopurine chemotherapy in about 20% of T-ALL and 5% of B-precursor ALL cases at relapse.
U0126
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: Tyrosine-protein phosphatase non-receptor type 11 (PTPN11) [9]
Sensitive Disease Acute lymphocytic leukemia [ICD-11: 2B33.0]
Sensitive Drug U0126
 Drug Info 
Molecule Alteration Missense mutation
p.E76K (c.226G>A)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.70  Å
PDB: 5EHR
Mutant Type Structure Method: X-ray diffraction Resolution: 2.62  Å
PDB: 6CRF
   Download The Information of Sequence       Download The Structure File   
RMSD: 3.04
TM score: 0.6516
Amino acid change:
E76K
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
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0
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S
G
M
M
T
T
S
S
R
R
R
R
W
W
F
F
H
H
P
P
10
|
N
N
I
I
T
T
G
G
V
V
E
E
A
A
E
E
N
N
L
L
20
|
L
L
L
L
T
T
R
R
G
G
V
V
D
D
G
G
S
S
F
F
30
|
L
L
A
A
R
R
P
P
S
S
K
K
S
S
N
N
P
P
G
G
40
|
D
D
F
F
T
T
L
L
S
S
V
V
R
R
R
R
N
N
G
G
50
|
A
A
V
V
T
T
H
H
I
I
K
K
I
I
Q
Q
N
N
T
T
60
|
G
G
D
D
Y
Y
Y
Y
D
D
L
L
Y
Y
G
G
G
G
E
E
70
|
K
K
F
F
A
A
T
T
L
L
A
A
E
K
L
L
V
V
Q
Q
80
|
Y
Y
Y
Y
M
M
E
E
H
H
H
H
G
G
Q
Q
L
L
K
K
90
|
E
E
K
K
N
N
G
G
D
D
V
V
I
I
E
E
L
L
K
K
100
|
Y
Y
P
P
L
L
N
N
C
C
A
A
D
D
P
P
T
T
S
S
110
|
E
E
R
R
W
W
F
F
H
H
G
G
H
H
L
L
S
S
G
G
120
|
K
K
E
E
A
A
E
E
K
K
L
L
L
L
T
T
E
E
K
K
130
|
G
G
K
K
H
H
G
G
S
S
F
F
L
L
V
V
R
R
E
E
140
|
S
S
Q
Q
S
S
H
H
P
P
G
G
D
D
F
F
V
V
L
L
150
|
S
S
V
V
R
R
T
T
G
G
D
D
D
D
K
K
G
G
E
E
160
|
S
S
N
N
D
D
G
G
K
K
S
S
K
K
V
V
T
T
H
H
170
|
V
V
M
M
I
I
R
R
C
C
Q
Q
E
E
L
L
K
K
Y
Y
180
|
D
D
V
V
G
G
G
G
G
G
E
E
R
R
F
F
D
D
S
S
190
|
L
L
T
T
D
D
L
L
V
V
E
E
H
H
Y
Y
K
K
K
K
200
|
N
N
P
P
M
M
V
V
E
E
T
T
L
L
G
G
T
T
V
V
210
|
L
L
Q
Q
L
L
K
K
Q
Q
P
P
L
L
N
N
T
T
T
T
220
|
R
R
I
I
N
N
A
A
A
A
E
E
I
I
E
E
S
S
R
R
230
|
V
V
R
R
E
E
L
L
S
S
K
K
L
L
A
A
E
E
T
T
240
|
T
T
D
D
K
K
V
V
K
K
Q
Q
G
G
F
F
W
W
E
E
250
|
E
E
F
F
E
E
T
T
L
L
Q
Q
Q
Q
Q
Q
E
E
C
C
260
|
K
K
L
L
L
L
Y
Y
S
S
R
R
K
K
E
E
G
G
Q
Q
270
|
R
R
Q
Q
E
E
N
N
K
K
N
N
K
K
N
N
R
R
Y
Y
280
|
K
K
N
N
I
I
L
L
P
P
F
F
D
D
H
H
T
T
R
R
290
|
V
V
V
V
L
L
H
H
D
D
G
G
D
D
P
P
N
N
E
E
300
|
P
P
V
V
S
S
D
D
Y
Y
I
I
N
N
A
A
N
N
I
I
310
|
I
I
M
M
P
P
E
E
F
F
E
E
T
T
K
K
C
C
N
N
320
|
N
N
S
S
K
K
P
P
K
K
K
K
S
S
Y
Y
I
I
A
A
330
|
T
T
Q
Q
G
G
C
C
L
L
Q
Q
N
N
T
T
V
V
N
N
340
|
D
D
F
F
W
W
R
R
M
M
V
V
F
F
Q
Q
E
E
N
N
350
|
S
S
R
R
V
V
I
I
V
V
M
M
T
T
T
T
K
K
E
E
360
|
V
V
E
E
R
R
G
G
K
K
S
S
K
K
C
C
V
V
K
K
370
|
Y
Y
W
W
P
P
D
D
E
E
Y
Y
A
A
L
L
K
K
E
E
380
|
Y
Y
G
G
V
V
M
M
R
R
V
V
R
R
N
N
V
V
K
K
390
|
E
E
S
S
A
A
A
A
H
H
D
D
Y
Y
T
T
L
L
R
R
400
|
E
E
L
L
K
K
L
L
S
S
K
K
V
V
G
G
Q
Q
G
G
410
|
N
N
T
T
E
E
R
R
T
T
V
V
W
W
Q
Q
Y
Y
H
H
420
|
F
F
R
R
T
T
W
W
P
P
D
D
H
H
G
G
V
V
P
P
430
|
S
S
D
D
P
P
G
G
G
G
V
V
L
L
D
D
F
F
L
L
440
|
E
E
E
E
V
V
H
H
H
H
K
K
Q
Q
E
E
S
S
I
I
450
|
M
M
D
D
A
A
G
G
P
P
V
V
V
V
V
V
H
H
C
C
460
|
S
S
A
A
G
G
I
I
G
G
R
R
T
T
G
G
T
T
F
F
470
|
I
I
V
V
I
I
D
D
I
I
L
L
I
I
D
D
I
I
I
I
480
|
R
R
E
E
K
K
G
G
V
V
D
D
C
C
D
D
I
I
D
D
490
|
V
V
P
P
K
K
T
T
I
I
Q
Q
M
M
V
V
R
R
S
S
500
|
Q
Q
R
R
S
S
G
G
M
M
V
V
Q
Q
T
T
E
E
A
A
510
|
Q
Q
Y
Y
R
R
F
F
I
I
Y
Y
M
M
A
A
V
V
Q
Q
520
|
H
H
Y
Y
I
I
E
E
T
T
L
L
Click to Show/Hide the Structure
Experimental Note Revealed Based on the Cell Line Data
Experiment for
Molecule Alteration		 Immunoblotting analysis
Experiment for
Drug Resistance		 Flow cytometry assay
Mechanism Description The missense mutation p.E76K (c.226G>A) in gene PTPN11 cause the sensitivity of U0126 by unusual activation of pro-survival pathway
References
Ref 1 Dasatinib as first-line treatment for adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. Blood. 2011 Dec 15;118(25):6521-8. doi: 10.1182/blood-2011-05-351403. Epub 2011 Sep 19.
Ref 2 Long-term follow-up of a phase 2 study of chemotherapy plus dasatinib for the initial treatment of patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. Cancer. 2015 Dec 1;121(23):4158-64. doi: 10.1002/cncr.29646. Epub 2015 Aug 26.
Ref 3 BCR-ABL gene mutations in relation to clinical resistance of Philadelphia-chromosome-positive leukaemia to STI571: a prospective study. Lancet. 2002 Feb 9;359(9305):487-91. doi: 10.1016/S0140-6736(02)07679-1.
Ref 4 Imatinib resistant BCR-ABL1 mutations at relapse in children with Ph+ ALL: a Children's Oncology Group (COG) study. Br J Haematol. 2012 May;157(4):507-10. doi: 10.1111/j.1365-2141.2012.09039.x. Epub 2012 Feb 2.
Ref 5 BCR-ABL1 mutations in patients with imatinib-resistant Philadelphia chromosome-positive leukemia by use of the PCR-Invader assay. Leuk Res. 2011 May;35(5):598-603. doi: 10.1016/j.leukres.2010.12.006. Epub 2011 Jan 15.
Ref 6 Mutational profiling of acute lymphoblastic leukemia with testicular relapse. J Hematol Oncol. 2017 Mar 2;10(1):65. doi: 10.1186/s13045-017-0434-y.
Ref 7 Mutational landscape, clonal evolution patterns, and role of RAS mutations in relapsed acute lymphoblastic leukemia. Proc Natl Acad Sci U S A. 2016 Oct 4;113(40):11306-11311. doi: 10.1073/pnas.1608420113. Epub 2016 Sep 21.
Ref 8 Ponatinib in refractory Philadelphia chromosome-positive leukemias. N Engl J Med. 2012 Nov 29;367(22):2075-88. doi: 10.1056/NEJMoa1205127.
Ref 9 Shp2E76K mutant confers cytokine-independent survival of TF-1 myeloid cells by up-regulating Bcl-XLJ Biol Chem. 2007 Dec 14;282(50):36463-73. doi: 10.1074/jbc.M705789200. Epub 2007 Oct 17.

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