Drug Information

Drug (ID: DG01891) and It's Reported Resistant Information
Name
SHP099
Synonyms
SHP099
    Click to Show/Hide
Drug Resistance Disease(s)
Disease(s) with Clinically Reported Resistance for This Drug (1 diseases)
Acute myeloid leukemia [ICD-11: 2A60]
[1]
Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (1 diseases)
Colorectal cancer [ICD-11: 2B91]
[2]
Target SHP2 PTN11_HUMAN [2]
Type(s) of Resistant Mechanism of This Drug
  UAPP: Unusual Activation of Pro-survival Pathway
Drug Resistance Data Categorized by Their Corresponding Diseases
ICD-02: Benign/in-situ/malignant neoplasm
Click to Show/Hide the Resistance Disease of This Class
Acute myeloid leukemia [ICD-11: 2A60]
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: Tyrosine-protein phosphatase non-receptor type 11 (PTPN11) [1]
Resistant Disease Acute myeloid leukemia [ICD-11: 2A60.0]
 Disease 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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10
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20
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30
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40
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50
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A
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60
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G
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Y
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D
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70
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A
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80
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90
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E
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100
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Y
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L
L
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C
A
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S
110
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E
E
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W
W
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H
H
G
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L
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G
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120
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K
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E
E
A
A
E
E
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L
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E
E
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130
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140
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150
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T
G
G
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D
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K
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E
E
160
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D
D
G
G
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K
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K
V
V
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H
H
170
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V
V
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M
I
I
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C
Q
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E
E
L
L
K
K
Y
Y
180
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D
D
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G
G
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G
E
E
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F
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190
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L
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L
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E
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200
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210
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L
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N
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T
T
220
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R
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I
I
N
N
A
A
A
A
E
E
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I
E
E
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R
230
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V
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R
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E
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A
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240
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250
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E
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260
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270
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E
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280
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290
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300
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A
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310
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I
I
M
M
P
P
E
E
F
F
E
E
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C
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N
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320
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N
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Y
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A
A
330
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T
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G
G
C
C
L
L
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N
N
T
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N
N
340
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D
D
F
F
W
W
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M
M
V
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F
F
Q
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E
E
N
N
350
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S
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E
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360
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G
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370
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380
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390
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400
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L
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410
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420
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430
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440
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450
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460
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G
G
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F
470
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480
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490
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500
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A
510
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Y
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F
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A
A
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Q
520
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H
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Y
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E
E
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T
L
L
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
In Vitro Model TF-1 cells Bone marrow Homo sapiens (Human) CVCL_0559
Mechanism Description The SHP2 variant carrying the potent activating mutation E76K exhibits an open-state structure, which induces drastic domain reorganization to expose the active site and eliminate the binding pocket for the allosteric inhibitor SHP099.
Key Molecule: Tyrosine-protein phosphatase non-receptor type 11 (PTPN11) [1]
Resistant Disease Acute myeloid leukemia [ICD-11: 2A60.0]
 Disease Info 
Molecule Alteration Missense mutation
p.D61Y (c.181G>T)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model TF-1 cells Bone marrow Homo sapiens (Human) CVCL_0559
Key Molecule: Tyrosine-protein phosphatase non-receptor type 11 (PTPN11) [1]
Resistant Disease Acute myeloid leukemia [ICD-11: 2A60.0]
 Disease Info 
Molecule Alteration Missense mutation
p.A72V (c.215C>T)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model TF-1 cells Bone marrow Homo sapiens (Human) CVCL_0559
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) [1]
Sensitive Disease Acute myeloid leukemia [ICD-11: 2A60.0]
 Disease Info 
Molecule Alteration Missense mutation
p.E69K (c.205G>A)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model TF-1 cells Bone marrow Homo sapiens (Human) CVCL_0559
Hematologic cancer [ICD-11: 2B3Z]
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 kinase JAK2 (JAK3) [2]
Sensitive Disease Hematologic Cancer [ICD-11: MG24.Y]
 Disease Info 
Molecule Alteration Missense mutation
p.V617F (c.1849G>T)
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation RAS/ERK signaling pathway Inhibition hsa01521
In Vitro Model MDA-MB-231 cells Breast Homo sapiens (Human) CVCL_0062
NCI-H2228 cells Lung Homo sapiens (Human) CVCL_1543
MDA-MB-468 cells Breast Homo sapiens (Human) CVCL_0419
A2058 cells Skin Homo sapiens (Human) CVCL_1059
KYSE520 cells Esophagus Homo sapiens (Human) CVCL_1355
KATO-3 cells Gastric Homo sapiens (Human) CVCL_0371
Sum52 cells Pleural effusion Homo sapiens (Human) CVCL_3425
NCI-H2170 cells Lung Homo sapiens (Human) CVCL_1535
NCI-H2170 cells Lung Homo sapiens (Human) CVCL_1535
H293 cells Kidney Homo sapiens (Human) N.A.
In Vivo Model Athymic nude mouse PDX model Mus musculus
Experiment for
Drug Resistance		 CellTitre-Glo assay; Crystal violet staining assay
Mechanism Description SHP099 suppresses RAS-ERK signalling to inhibit the proliferation of receptor-tyrosine-kinase-driven human cancer cells in vitro and is efficacious in mouse tumour xenograft models.
Colorectal cancer [ICD-11: 2B91]
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) [2]
Resistant Disease Colorectal cancer [ICD-11: 2B91.1]
 Disease 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
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420
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430
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440
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460
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470
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480
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A
490
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P
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A
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500
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E
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G
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V
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R
510
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V
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L
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F
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520
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P
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A
A
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T
T
530
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Q
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W
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C
C
E
E
G
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Y
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H
540
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H
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E
550
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A
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560
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A
A
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G
G
M
M
D
D
Y
Y
L
L
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H
A
A
570
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K
K
S
S
I
I
I
I
H
H
R
R
D
D
L
L
K
K
S
S
580
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N
N
N
N
I
I
F
F
L
L
H
H
E
E
D
D
L
L
T
T
590
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V
V
K
K
I
I
G
G
D
D
F
F
G
G
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A
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T
600
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V
E
K
K
S
S
R
R
W
W
S
S
G
G
S
S
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610
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F
F
E
E
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Q
L
L
S
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G
G
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I
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L
W
W
620
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M
M
A
A
P
P
E
E
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V
I
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R
M
M
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D
D
630
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K
K
N
N
P
P
Y
Y
S
S
F
F
Q
Q
S
S
D
D
V
V
640
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Y
Y
A
A
F
F
G
G
I
I
V
V
L
L
Y
Y
E
E
L
L
650
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M
M
T
T
G
G
Q
Q
L
L
P
P
Y
Y
S
S
N
N
I
I
660
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N
N
N
N
R
R
D
D
Q
Q
I
I
I
I
F
F
M
M
V
V
670
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G
G
R
R
G
G
Y
Y
L
L
S
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P
D
D
L
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S
680
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K
K
V
V
R
R
S
S
N
N
C
C
P
P
K
K
A
A
M
M
690
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K
K
R
R
L
L
M
M
A
A
E
E
C
C
L
L
K
K
K
K
700
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K
K
R
R
D
D
E
E
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R
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L
L
F
F
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P
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710
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I
I
L
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A
A
S
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I
I
E
E
L
L
L
L
A
A
R
R
720
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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 RAS/ERK signaling pathway Inhibition hsa01521
In Vitro Model MDA-MB-231 cells Breast Homo sapiens (Human) CVCL_0062
NCI-H2228 cells Lung Homo sapiens (Human) CVCL_1543
MDA-MB-468 cells Breast Homo sapiens (Human) CVCL_0419
A2058 cells Skin Homo sapiens (Human) CVCL_1059
KYSE520 cells Esophagus Homo sapiens (Human) CVCL_1355
KATO-3 cells Gastric Homo sapiens (Human) CVCL_0371
Sum52 cells Pleural effusion Homo sapiens (Human) CVCL_3425
NCI-H2170 cells Lung Homo sapiens (Human) CVCL_1535
NCI-H2170 cells Lung Homo sapiens (Human) CVCL_1535
H293 cells Kidney Homo sapiens (Human) N.A.
In Vivo Model Athymic nude mouse PDX model Mus musculus
Experiment for
Drug Resistance		 CellTitre-Glo assay; Crystal violet staining assay
Mechanism Description SHP099 suppresses RAS-ERK signalling to inhibit the proliferation of receptor-tyrosine-kinase-driven human cancer cells in vitro and is efficacious in mouse tumour xenograft models.
Thyroid cancer [ICD-11: 2D10]
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) [3]
Sensitive Disease Thyroid gland cancer [ICD-11: 2D10.0]
 Disease Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation MAPK/ERK signaling pathway Inhibition hsa04011
In Vitro Model K1 cells Thyroid Homo sapiens (Human) CVCL_2537
BCPAP cells Thyroid Homo sapiens (Human) CVCL_0153
KTC-1 cells Thyroid Homo sapiens (Human) CVCL_6300
8305C cells Thyroid Homo sapiens (Human) CVCL_1053
BHT-101 cells Thyroid gland Homo sapiens (Human) CVCL_1085
In Vivo Model Mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Western blot assay; RT-qPCR
Experiment for
Drug Resistance		 Cell proliferation capacity assay
Mechanism Description In treating thyroid cancer cells with vemurafenib, we have detected reactivation of the MAPK/ERK signaling pathway as a result of the release of multiple receptor tyrosine kinases (RTKs) from the negative feedback of ERK phosphorylation. SHP2 is an important target protein downstream of the RTK signaling pathway. Decreasing it through SHP2 knockdown or the use of an inhibitor of SHP2 (SHP099) was found to significantly increase the early sensitivity and reverse the late resistance to vemurafenib in BRAFV600E mutant thyroid cancer cells.Blocking SHP2 reverses the reactivation of the MAPK/ERK signaling pathway caused by the activation of RTKs and improves the sensitivity of thyroid cancer to vemurafenib.
References
Ref 1 Selective inhibition of leukemia-associated SHP2(E69K) mutant by the allosteric SHP2 inhibitor SHP099Leukemia. 2018 May;32(5):1246-1249. doi: 10.1038/s41375-018-0020-5. Epub 2018 Jan 30.
Ref 2 Allosteric inhibition of SHP2 phosphatase inhibits cancers driven by receptor tyrosine kinasesNature. 2016 Jul 7;535(7610):148-52. doi: 10.1038/nature18621. Epub 2016 Jun 29.
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