Drug Information

Drug (ID: DG01505) and It's Reported Resistant Information
Name
Selumetinib
Synonyms
Selumetinib; 606143-52-6; AZD6244; AZD 6244; ARRY-142886; 5-[(4-BROMO-2-CHLOROPHENYL)AMINO]-4-FLUORO-N-(2-HYDROXYETHOXY)-1-METHYL-1H-BENZIMIDAZOLE-6-CARBOXAMIDE; AZD-6244; Selumetinib (AZD6244); ARRY 142886; AZD6244 (Selumetinib); ARRY-886; UNII-6UH91I579U; 5-((4-bromo-2-chlorophenyl)amino)-4-fluoro-N-(2-hydroxyethoxy)-1-methyl-1H-benzo[d]imidazole-6-carboxamide; 5-(4-broMo-2-chlorophenylaMino)-4-fluoro-N-(2-hydroxyethoxy)-1-Methyl-1H-benzo[d]iMidazole-6-carboxaMide; CHEMBL1614701; CHEBI:90227; 6UH91I579U; NCGC00189073-01; NCGC00189073-02; C17H15BrClFN4O3; 6-(4-bromo-2-chloroanilino)-7-fluoro-N-(2-hydroxyethoxy)-3-methylbenzimidazole-5-carboxamide; DSSTox_CID_28870; DSSTox_RID_83139; DSSTox_GSID_48944; 1H-Benzimidazole-6-carboxamide, 5-[(4-bromo-2-chlorophenyl)amino]-4-fluoro-N-(2-hydroxyethoxy)-1-methyl-; 6-[(4-bromo-2-chlorophenyl)amino]-7-fluoro-N-(2-hydroxyethoxy)-3-methylbenzimidazole-5-carboxamide; AZD 6244;5-((4-Bromo-2-chlorophenyl)amino)-4-fluoro-N-(2-hydroxyethoxy)-1-methyl-1H-benzo[d]imidazole-6-carboxamide;6-(4-bromo-2-chlorophenylamino)-7-fluoro-N-(2-hydroxyethoxy)-3-methyl-3H-benzo[d]imidazole-5-carboxamide; CAS-606143-52-6; ARRY142886; Selumetinib [USAN:INN]; selumetinibum; Koselugo; 1H-Benzimidazole-6-carboxamide, 5-((4-bromo-2-chlorophenyl)amino)-4-fluoro-N-(2-hydroxyethoxy)-1-methyl-; 3EW; Selumetinib (USAN/INN); AZD6244 - Selumetinib; AZD 6244 (Selumetinib); SCHEMBL155456; GTPL5665; QCR-91; Selumetinib, ARRY-142886; DTXSID3048944; EX-A020; SYN1016; BCPP000367; HMS3244G03; HMS3244G04; HMS3244H03; HMS3265K01; HMS3265K02; HMS3265L01; HMS3265L02; HMS3654O03; NSC 741O78; AOB87732; BCP01739; Tox21_113362; BDBM50355497; MFCD11977472; NSC741078; NSC800882; s1008; ZINC31773258; AKOS015904255; Tox21_113362_1; BCP9000354; CCG-264774; CS-0059; DB11689; EX-8621; NSC-741078; NSC-800882; SB14707; NCGC00189073-07; AC-25059; AM808016; AZD6244,Selumetinib, ARRY-142886; BC004624; HY-50706; Selumetinib (ARRY142886/AZD6244); AZD6244 (Selumetinib,ARRY-142886); FT-0674552; SW202561-3; X2640; D09666; 143A526; Q-101405; Q7448840; BRD-K57080016-001-01-9; 5-[(4-bromo-2-chlorophenyl)amino]-4-fluoro-N-(2-hydroxyethoxy)-1-methyl-1H-1,3-benzodiazole-6-carboxamide; 6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxy -ethoxy)-amide; 6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxy-ethoxy)-amide; 6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid(2-hydroxy-ethoxy)-amide; 6-(4-bromo-2-chlorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxyethoxy)-amide; 6-(4-bromo-2-chlorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid(2-hydroxyethoxy)-amide; 6-(4-bromo-2chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxy-ethoxy)-amide
    Click to Show/Hide
Indication
In total 2 Indication(s)
Parkinson disease [ICD-11: 8A00]
Phase 3
[1]
Parkinson disease [ICD-11: 8A00]
Phase 3
[1]
Structure
Drug Resistance Disease(s)
Disease(s) with Clinically Reported Resistance for This Drug (1 diseases)
Acute myeloid leukemia [ICD-11: 2A60]
[2]
Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (6 diseases)
Colorectal cancer [ICD-11: 2B91]
[3]
Bladder cancer [ICD-11: 2C94]
[5]
Endometrial cancer [ICD-11: 2C76]
[6]
Lung cancer [ICD-11: 2C25]
[7]
Melanoma [ICD-11: 2C30]
[1]
Solid tumour/cancer [ICD-11: 2A00-2F9Z]
[8]
Disease(s) with Resistance Information Validated by in-vivo Model for This Drug (1 diseases)
Esophageal cancer [ICD-11: 2B70]
[4]
Target 5-HT 2A receptor (HTR2A) 5HT2A_HUMAN [9]
Click to Show/Hide the Molecular Information and External Link(s) of This Drug
Formula
6
IsoSMILES
CN1C=NC2=C1C=C(C(=C2F)NC3=C(C=C(C=C3)Br)Cl)C(=O)NOCCO
InChI
InChI=1S/C17H15BrClFN4O3/c1-24-8-21-16-13(24)7-10(17(26)23-27-5-4-25)15(14(16)20)22-12-3-2-9(18)6-11(12)19/h2-3,6-8,22,25H,4-5H2,1H3,(H,23,26)
InChIKey
CYOHGALHFOKKQC-UHFFFAOYSA-N
PubChem CID
10127622
ChEBI ID
CHEBI:90227
TTD Drug ID
D0J8JP
DrugBank ID
DB11689
Type(s) of Resistant Mechanism of This Drug due to Structure Alteration
  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
Brain cancer [ICD-11: 2A00]
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]
 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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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]
 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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Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
Solid tumour/cancer [ICD-11: 2A00-2F9Z]
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: MAPK/ERK kinase 1 (MEK1) [8]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
 Disease Info 
Molecule Alteration Missense mutation
p.C121S (c.361T>A)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.70  Å
PDB: 7B7R
Mutant Type Structure Method: X-ray diffraction Resolution: 2.01  Å
PDB: 7F2X
   Download The Information of Sequence       Download The Structure File   
RMSD: 2.36
TM score: 0.87257
Amino acid change:
C121S
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
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N
200
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C
C
D
D
F
F
210
|
G
G
V
V
S
S
G
G
Q
Q
L
L
I
I
D
D
S
S
M
M
220
|
A
A
N
N
S
S
F
F
V
V
G
G
T
T
R
R
S
S
Y
Y
230
|
M
M
S
S
P
P
E
E
R
R
L
L
Q
Q
G
G
T
T
H
H
240
|
Y
Y
S
S
V
V
Q
Q
S
S
D
D
I
I
W
W
S
S
M
M
250
|
G
G
L
L
S
S
L
L
V
V
E
E
M
M
A
A
V
V
G
G
260
|
R
R
Y
Y
P
P
I
I
-
G
-
S
-
G
-
S
-
G
-
S
270
|
-
M
-
A
-
I
-
F
-
E
-
L
-
L
-
D
-
Y
-
I
280
|
-
V
-
N
-
E
-
P
-
P
-
P
-
K
-
L
-
P
-
S
290
|
-
G
-
V
-
F
-
S
-
L
-
E
-
F
-
Q
-
D
-
F
300
|
-
V
-
N
G
K
S
C
G
L
S
I
G
K
S
N
M
P
A
A
310
|
I
E
F
R
E
A
L
D
L
L
D
K
Y
Q
I
L
V
M
N
V
320
|
E
H
P
A
P
F
P
I
K
K
L
R
P
S
S
D
G
A
V
E
330
|
F
E
S
V
L
D
E
F
F
A
Q
G
D
W
F
L
V
C
N
S
340
|
K
T
C
I
L
G
I
L
K
N
N
Q
P
P
A
S
E
T
R
P
350
|
A
T
D
H
L
A
K
A
Q
G
L
E
M
G
V
H
H
H
A
H
360
|
F
H
I
H
K
H
R
-
S
-
D
-
A
-
E
-
E
-
V
-
370
|
D
-
F
-
A
-
G
-
W
-
L
-
C
-
S
-
T
-
I
-
380
|
G
-
L
-
N
-
Q
-
Click to Show/Hide the Structure
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model HEK293 cells Kidney Homo sapiens (Human) CVCL_0045
Experiment for
Molecule Alteration		 SDS-PAGE assay
Mechanism Description The missense mutation p.C121S (c.361T>A) in gene MAP2K1 cause the sensitivity of Selumetinib by unusual activation of pro-survival pathway
Lung cancer [ICD-11: 2C25]
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: Epidermal growth factor receptor (EGFR) [7]
Resistant Disease Lung adenocarcinoma [ICD-11: 2C25.0]
 Disease Info 
Molecule Alteration Missense mutation
p.T790M (c.2369C>T)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 3.10  Å
PDB: 2J6M
Mutant Type Structure Method: X-ray diffraction Resolution: 3.05  Å
PDB: 2JIU
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.57
TM score: 0.92063
Amino acid change:
T790M
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
-
S
G
G
E
E
A
A
P
P
700
|
N
N
Q
Q
A
A
L
L
L
L
R
R
I
I
L
L
K
K
E
E
710
|
T
T
E
E
F
F
K
K
K
K
I
I
K
K
V
V
L
L
G
G
720
|
S
S
G
G
A
A
F
F
G
G
T
T
V
V
Y
Y
K
K
G
G
730
|
L
L
W
W
I
I
P
P
E
E
G
G
E
E
K
K
V
V
K
K
740
|
I
I
P
P
V
V
A
A
I
I
K
K
E
E
L
L
R
R
E
E
750
|
A
A
T
T
S
S
P
P
K
K
A
A
N
N
K
K
E
E
I
I
760
|
L
L
D
D
E
E
A
A
Y
Y
V
V
M
M
A
A
S
S
V
V
770
|
D
D
N
N
P
P
H
H
V
V
C
C
R
R
L
L
L
L
G
G
780
|
I
I
C
C
L
L
T
T
S
S
T
T
V
V
Q
Q
L
L
I
I
790
|
T
M
Q
Q
L
L
M
M
P
P
F
F
G
G
C
C
L
L
L
L
800
|
D
D
Y
Y
V
V
R
R
E
E
H
H
K
K
D
D
N
N
I
I
810
|
G
G
S
S
Q
Q
Y
Y
L
L
L
L
N
N
W
W
C
C
V
V
820
|
Q
Q
I
I
A
A
K
K
G
G
M
M
N
N
Y
Y
L
L
E
E
830
|
D
D
R
R
R
R
L
L
V
V
H
H
R
R
D
D
L
L
A
A
840
|
A
A
R
R
N
N
V
V
L
L
V
V
K
K
T
T
P
P
Q
Q
850
|
H
H
V
V
K
K
I
I
T
T
D
D
F
F
G
G
L
L
A
A
860
|
K
K
L
L
L
L
G
G
A
A
E
E
E
E
K
K
E
E
Y
Y
870
|
H
H
A
A
E
E
G
G
G
G
K
K
V
V
P
P
I
I
K
K
880
|
W
W
M
M
A
A
L
L
E
E
S
S
I
I
L
L
H
H
R
R
890
|
I
I
Y
Y
T
T
H
H
Q
Q
S
S
D
D
V
V
W
W
S
S
900
|
Y
Y
G
G
V
V
T
T
V
V
W
W
E
E
L
L
M
M
T
T
910
|
F
F
G
G
S
S
K
K
P
P
Y
Y
D
D
G
G
I
I
P
P
920
|
A
A
S
S
E
E
I
I
S
S
S
S
I
I
L
L
E
E
K
K
930
|
G
G
E
E
R
R
L
L
P
P
Q
Q
P
P
P
P
I
I
C
C
940
|
T
T
I
I
D
D
V
V
Y
Y
M
M
I
I
M
M
V
V
K
K
950
|
C
C
W
W
M
M
I
I
D
D
A
A
D
D
S
S
R
R
P
P
960
|
K
K
F
F
R
R
E
E
L
L
I
I
I
I
E
E
F
F
S
S
970
|
K
K
M
M
A
A
R
R
D
D
P
P
Q
Q
R
R
Y
Y
L
L
980
|
V
V
I
I
Q
Q
G
G
D
D
E
E
R
R
M
M
H
H
L
L
990
|
P
P
S
S
P
P
T
T
D
D
S
S
N
N
F
F
Y
Y
R
R
1000
|
A
A
L
L
M
M
D
D
E
E
E
E
D
D
M
M
D
D
D
D
1010
|
V
V
V
V
D
D
A
A
D
D
E
E
Y
Y
L
L
I
I
P
P
1020
|
Q
Q
Q
Q
G
G
Click to Show/Hide the Structure
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model NCI-H1975 cells Lung Homo sapiens (Human) CVCL_1511
In Vivo Model BALB/C nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis; Immunohistochemistry assay
Experiment for
Drug Resistance		 MTT assay
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Unusual Activation of Pro-survival Pathway (UAPP) Click to Show/Hide
Key Molecule: GTPase Nras (NRAS) [10]
Sensitive Disease Lung adenocarcinoma [ICD-11: 2C25.0]
 Disease 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
In Vitro Model H1299 cells Lung Homo sapiens (Human) CVCL_0060
SW1271 cells Lung Homo sapiens (Human) CVCL_1716
H2347 cells Lung Homo sapiens (Human) CVCL_1550
H2087 cells Lymph node Homo sapiens (Human) CVCL_1524
Experiment for
Molecule Alteration		 Immunoblotting analysis
Experiment for
Drug Resistance		 Cell Titer blue reagent assay
Mechanism Description The missense mutation p.Q61K (c.181C>A) in gene NRAS cause the sensitivity of Selumetinib by unusual activation of pro-survival pathway
Melanoma [ICD-11: 2C30]
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) [1]
Sensitive Disease Melanoma [ICD-11: 2C30.0]
 Disease 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 Revealed Based on the Cell Line Data
In Vitro Model A375 cells Skin Homo sapiens (Human) CVCL_0132
Sk-Mel28 cells Skin Homo sapiens (Human) CVCL_0526
A2058 cells Skin Homo sapiens (Human) CVCL_1059
A375 cells Skin Homo sapiens (Human) CVCL_0132
A375 cells Skin Homo sapiens (Human) CVCL_0132
A375 cells Skin Homo sapiens (Human) CVCL_0132
WM2664 cells Skin Homo sapiens (Human) CVCL_2765
SkMEL 30 cells Skin Homo sapiens (Human) CVCL_0039
SkMEL 2 cells Skin Homo sapiens (Human) CVCL_0069
SH4 cells Skin Mus musculus (Mouse) CVCL_7702
MEXF-535 cells Skin Homo sapiens (Human) N.A.
MEXF-1792 cells Skin Homo sapiens (Human) N.A.
MEXF-1341 cells Skin Homo sapiens (Human) N.A.
M14 cells Hypodermis Homo sapiens (Human) CVCL_1395
GAK cells Lnguinal lymph node Homo sapiens (Human) CVCL_1225
Colo829 cells Skin Homo sapiens (Human) CVCL_1137
In Vivo Model Female NIH nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis; Crystallization assay; X-ray data collection and structure determination assay
Experiment for
Drug Resistance		 CellTiter-Glo assay; Enzymatic kinase assay
Key Molecule: GTPase Nras (NRAS) [11]
Sensitive Disease Melanoma [ICD-11: 2C30.0]
 Disease 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
In Vitro Model Skin N.A.
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 MTS assay
Mechanism Description The missense mutation p.Q61K (c.181C>A) in gene NRAS cause the sensitivity of Selumetinib by aberration of the drug's therapeutic target
Key Molecule: GTPase Nras (NRAS) [12]
Sensitive Disease Melanoma [ICD-11: 2C30.0]
 Disease Info 
Molecule Alteration Missense mutation
p.Q61R (c.182A>G)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.59  Å
PDB: 8TBI
Mutant Type Structure Method: X-ray diffraction Resolution: 1.24  Å
PDB: 7F68
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.46
TM score: 0.94384
Amino acid change:
Q61R
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
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
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
R
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
D
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
-
L
-
N
-
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
Experiment for
Drug Resistance		 MTD assay
Mechanism Description The missense mutation p.Q61R (c.182A>G) in gene NRAS cause the sensitivity of Selumetinib by unusual activation of pro-survival pathway
Key Molecule: GTPase Nras (NRAS) [1]
Sensitive Disease Melanoma [ICD-11: 2C30.0]
 Disease Info 
Molecule Alteration Missense mutation
p.G13D (c.38G>A)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.01  Å
PDB: 6P0Z
Mutant Type Structure Method: X-ray diffraction Resolution: 1.40  Å
PDB: 8BLR
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.48
TM score: 0.8385
Amino acid change:
G13D
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
0
|
-
G
-
G
T
T
E
E
Y
Y
K
K
L
L
V
V
V
V
V
V
10
|
G
G
A
A
G
G
G
D
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 Revealed Based on the Cell Line Data
In Vitro Model A375 cells Skin Homo sapiens (Human) CVCL_0132
Sk-Mel28 cells Skin Homo sapiens (Human) CVCL_0526
A2058 cells Skin Homo sapiens (Human) CVCL_1059
A375 cells Skin Homo sapiens (Human) CVCL_0132
A375 cells Skin Homo sapiens (Human) CVCL_0132
A375 cells Skin Homo sapiens (Human) CVCL_0132
WM2664 cells Skin Homo sapiens (Human) CVCL_2765
SkMEL 30 cells Skin Homo sapiens (Human) CVCL_0039
SkMEL 2 cells Skin Homo sapiens (Human) CVCL_0069
SH4 cells Skin Mus musculus (Mouse) CVCL_7702
MEXF-535 cells Skin Homo sapiens (Human) N.A.
MEXF-1792 cells Skin Homo sapiens (Human) N.A.
MEXF-1341 cells Skin Homo sapiens (Human) N.A.
M14 cells Hypodermis Homo sapiens (Human) CVCL_1395
GAK cells Lnguinal lymph node Homo sapiens (Human) CVCL_1225
Colo829 cells Skin Homo sapiens (Human) CVCL_1137
In Vivo Model Female NIH nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis; Crystallization assay; X-ray data collection and structure determination assay
Experiment for
Drug Resistance		 CellTiter-Glo assay; Enzymatic kinase assay
Key Molecule: Guanine nucleotide-binding protein subunit alpha-11 (GNA11) [13]
Sensitive Disease Melanoma [ICD-11: 2C30.0]
 Disease Info 
Molecule Alteration Missense mutation
p.Q209L (c.626A>T)
 Molecule Info 
Wild Type Structure Method: Electron microscopy Resolution: 3.50  Å
PDB: 6VU5
Mutant Type Structure Method: Electron microscopy Resolution: 2.90  Å
PDB: 7F6G
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.91
TM score: 0.72705
Amino acid change:
Q209L
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
-
M
-
H
-
H
-
H
-
H
-
H
-
H
-
H
-
H
0
|
-
H
M
H
T
T
L
L
E
E
S
S
I
I
M
M
A
A
C
C
10
|
C
C
L
L
S
S
E
E
E
E
A
A
K
K
E
E
A
A
R
R
20
|
R
R
I
I
N
N
D
D
E
E
I
I
E
E
R
R
Q
Q
L
L
30
|
R
R
R
R
D
D
K
K
R
R
D
D
A
A
R
R
R
R
E
E
40
|
L
L
K
K
L
L
L
L
L
L
L
L
G
G
T
T
G
G
E
E
50
|
S
S
G
G
K
K
S
S
T
T
F
F
I
I
K
K
Q
Q
M
M
60
|
R
R
I
I
I
I
H
H
G
G
S
S
G
G
Y
Y
S
S
D
D
70
|
E
E
D
D
K
K
R
R
G
G
F
F
T
T
K
K
L
L
V
V
80
|
Y
Y
Q
Q
N
N
I
I
F
F
T
T
A
A
M
M
Q
Q
A
A
90
|
M
M
I
I
R
R
A
A
M
M
D
D
T
T
L
L
K
K
I
I
100
|
P
P
Y
Y
K
K
Y
Y
E
E
H
H
N
N
K
K
A
A
H
H
110
|
A
A
Q
Q
L
L
V
V
R
R
E
E
V
V
D
D
V
V
E
E
120
|
K
K
V
V
S
S
A
A
F
F
E
E
N
N
P
P
Y
Y
V
V
130
|
D
D
A
A
I
I
K
K
S
S
L
L
W
W
N
N
D
D
P
P
140
|
G
G
I
I
Q
Q
E
E
C
C
Y
Y
D
D
R
R
R
R
R
R
150
|
E
E
Y
Y
Q
Q
L
L
S
S
D
D
S
S
T
T
K
K
Y
Y
160
|
Y
Y
L
L
N
N
D
D
L
L
D
D
R
R
V
V
A
A
D
D
170
|
P
P
A
A
Y
Y
L
L
P
P
T
T
Q
Q
Q
Q
D
D
V
V
180
|
L
L
R
R
V
V
R
Q
V
V
P
P
T
T
T
T
G
G
I
I
190
|
I
I
E
E
Y
Y
P
P
F
F
D
D
L
L
Q
Q
S
S
V
V
200
|
I
I
F
F
R
R
M
M
V
V
D
D
V
V
G
G
G
G
Q
L
210
|
R
R
S
S
E
E
R
R
R
R
K
K
W
W
I
I
H
H
C
C
220
|
F
F
E
E
N
N
V
V
T
T
S
S
I
I
M
M
F
F
L
L
230
|
V
V
A
A
L
L
S
S
E
E
Y
Y
D
D
Q
Q
V
V
L
L
240
|
V
V
E
E
S
S
D
D
N
N
E
E
N
N
R
R
M
M
E
E
250
|
E
E
S
S
K
K
A
A
L
L
F
F
R
R
T
T
I
I
I
I
260
|
T
T
Y
Y
P
P
W
W
F
F
Q
Q
N
N
S
S
S
S
V
V
270
|
I
I
L
L
F
F
L
L
N
N
K
K
K
K
D
D
L
L
L
L
280
|
E
E
E
E
K
K
I
I
M
M
Y
Y
S
S
H
H
L
L
V
V
290
|
D
D
Y
Y
F
F
P
P
E
E
Y
Y
D
D
G
G
P
P
Q
Q
300
|
R
R
D
D
A
A
Q
Q
A
A
A
A
R
R
E
E
F
F
I
I
310
|
L
L
K
K
M
M
F
F
V
V
D
D
L
L
N
N
P
P
D
D
320
|
S
S
D
D
K
K
I
I
I
I
Y
Y
S
S
H
H
F
F
T
T
330
|
C
C
A
A
T
T
D
D
T
T
E
E
N
N
I
I
R
R
F
F
340
|
V
V
F
F
A
A
A
A
V
V
K
K
D
D
T
T
I
I
L
L
350
|
Q
Q
L
L
N
N
L
L
K
K
E
E
Y
Y
N
N
L
L
V
V
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
Key Molecule: Guanine nucleotide-binding protein subunit alpha-11 (GNA11) [13]
Sensitive Disease Melanoma [ICD-11: 2C30.0]
 Disease Info 
Molecule Alteration Missense mutation
p.Q209L (c.626A>T)
 Molecule Info 
Wild Type Structure Method: Electron microscopy Resolution: 3.50  Å
PDB: 6VU5
Mutant Type Structure Method: Electron microscopy Resolution: 2.90  Å
PDB: 7F6G
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.91
TM score: 0.72705
Amino acid change:
Q209L
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
-
M
-
H
-
H
-
H
-
H
-
H
-
H
-
H
-
H
0
|
-
H
M
H
T
T
L
L
E
E
S
S
I
I
M
M
A
A
C
C
10
|
C
C
L
L
S
S
E
E
E
E
A
A
K
K
E
E
A
A
R
R
20
|
R
R
I
I
N
N
D
D
E
E
I
I
E
E
R
R
Q
Q
L
L
30
|
R
R
R
R
D
D
K
K
R
R
D
D
A
A
R
R
R
R
E
E
40
|
L
L
K
K
L
L
L
L
L
L
L
L
G
G
T
T
G
G
E
E
50
|
S
S
G
G
K
K
S
S
T
T
F
F
I
I
K
K
Q
Q
M
M
60
|
R
R
I
I
I
I
H
H
G
G
S
S
G
G
Y
Y
S
S
D
D
70
|
E
E
D
D
K
K
R
R
G
G
F
F
T
T
K
K
L
L
V
V
80
|
Y
Y
Q
Q
N
N
I
I
F
F
T
T
A
A
M
M
Q
Q
A
A
90
|
M
M
I
I
R
R
A
A
M
M
D
D
T
T
L
L
K
K
I
I
100
|
P
P
Y
Y
K
K
Y
Y
E
E
H
H
N
N
K
K
A
A
H
H
110
|
A
A
Q
Q
L
L
V
V
R
R
E
E
V
V
D
D
V
V
E
E
120
|
K
K
V
V
S
S
A
A
F
F
E
E
N
N
P
P
Y
Y
V
V
130
|
D
D
A
A
I
I
K
K
S
S
L
L
W
W
N
N
D
D
P
P
140
|
G
G
I
I
Q
Q
E
E
C
C
Y
Y
D
D
R
R
R
R
R
R
150
|
E
E
Y
Y
Q
Q
L
L
S
S
D
D
S
S
T
T
K
K
Y
Y
160
|
Y
Y
L
L
N
N
D
D
L
L
D
D
R
R
V
V
A
A
D
D
170
|
P
P
A
A
Y
Y
L
L
P
P
T
T
Q
Q
Q
Q
D
D
V
V
180
|
L
L
R
R
V
V
R
Q
V
V
P
P
T
T
T
T
G
G
I
I
190
|
I
I
E
E
Y
Y
P
P
F
F
D
D
L
L
Q
Q
S
S
V
V
200
|
I
I
F
F
R
R
M
M
V
V
D
D
V
V
G
G
G
G
Q
L
210
|
R
R
S
S
E
E
R
R
R
R
K
K
W
W
I
I
H
H
C
C
220
|
F
F
E
E
N
N
V
V
T
T
S
S
I
I
M
M
F
F
L
L
230
|
V
V
A
A
L
L
S
S
E
E
Y
Y
D
D
Q
Q
V
V
L
L
240
|
V
V
E
E
S
S
D
D
N
N
E
E
N
N
R
R
M
M
E
E
250
|
E
E
S
S
K
K
A
A
L
L
F
F
R
R
T
T
I
I
I
I
260
|
T
T
Y
Y
P
P
W
W
F
F
Q
Q
N
N
S
S
S
S
V
V
270
|
I
I
L
L
F
F
L
L
N
N
K
K
K
K
D
D
L
L
L
L
280
|
E
E
E
E
K
K
I
I
M
M
Y
Y
S
S
H
H
L
L
V
V
290
|
D
D
Y
Y
F
F
P
P
E
E
Y
Y
D
D
G
G
P
P
Q
Q
300
|
R
R
D
D
A
A
Q
Q
A
A
A
A
R
R
E
E
F
F
I
I
310
|
L
L
K
K
M
M
F
F
V
V
D
D
L
L
N
N
P
P
D
D
320
|
S
S
D
D
K
K
I
I
I
I
Y
Y
S
S
H
H
F
F
T
T
330
|
C
C
A
A
T
T
D
D
T
T
E
E
N
N
I
I
R
R
F
F
340
|
V
V
F
F
A
A
A
A
V
V
K
K
D
D
T
T
I
I
L
L
350
|
Q
Q
L
L
N
N
L
L
K
K
E
E
Y
Y
N
N
L
L
V
V
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
Endometrial cancer [ICD-11: 2C76]
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: Fibroblast growth factor receptor 2 (FGFR2) [6]
Resistant Disease Endometrial adenocarcinoma [ICD-11: 2C76.0]
 Disease Info 
Molecule Alteration Missense mutation
p.S252W (c.755C>G)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 3.88  Å
PDB: 4J23
Mutant Type Structure Method: X-ray diffraction Resolution: 2.70  Å
PDB: 1II4
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.81
TM score: 0.89346
Amino acid change:
S252W
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
M
-
N
N
S
S
N
N
150
|
N
N
K
K
R
R
A
A
P
P
Y
Y
W
W
T
T
N
N
T
T
160
|
E
E
K
K
M
M
E
E
K
K
R
R
L
L
H
H
A
A
V
V
170
|
P
P
A
A
A
A
N
N
T
T
V
V
K
K
F
F
R
R
C
C
180
|
P
P
A
A
G
G
G
G
N
N
P
P
M
M
P
P
T
T
M
M
190
|
R
R
W
W
L
L
K
K
N
N
G
G
K
K
E
E
F
F
K
K
200
|
Q
Q
E
E
H
H
R
R
I
I
G
G
G
G
Y
Y
K
K
V
V
210
|
R
R
N
N
Q
Q
H
H
W
W
S
S
L
L
I
I
M
M
E
E
220
|
S
S
V
V
V
V
P
P
S
S
D
D
K
K
G
G
N
N
Y
Y
230
|
T
T
C
C
V
V
V
V
E
E
N
N
E
E
Y
Y
G
G
S
S
240
|
I
I
N
N
H
H
T
T
Y
Y
H
H
L
L
D
D
V
V
V
V
250
|
E
E
R
R
S
W
P
P
H
H
R
R
P
P
I
I
L
L
Q
Q
260
|
A
A
G
G
L
L
P
P
A
A
N
N
A
A
S
S
T
T
V
V
270
|
V
V
G
G
G
G
D
D
V
V
E
E
F
F
V
V
C
C
K
K
280
|
V
V
Y
Y
S
S
D
D
A
A
Q
Q
P
P
H
H
I
I
Q
Q
290
|
W
W
I
I
K
K
H
H
V
V
E
E
K
K
N
N
G
G
S
S
300
|
K
K
Y
Y
G
G
P
P
D
D
G
G
L
L
P
P
Y
Y
L
L
310
|
K
K
V
V
L
L
K
K
A
A
A
A
G
G
V
V
N
N
T
T
320
|
T
T
D
D
K
K
E
E
I
I
E
E
V
V
L
L
Y
Y
I
I
330
|
R
R
N
N
V
V
T
T
F
F
E
E
D
D
A
A
G
G
E
E
340
|
Y
Y
T
T
C
C
L
L
A
A
G
G
N
N
S
S
I
I
G
G
350
|
I
I
S
S
F
F
H
H
S
S
A
A
W
W
L
L
T
T
V
V
360
|
L
L
P
P
A
A
P
P
G
G
R
R
E
E
L
-
E
-
Click to Show/Hide the Structure
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model HCT116 cells Colon Homo sapiens (Human) CVCL_0291
NCI-N87 cells Gastric Homo sapiens (Human) CVCL_1603
MkN-45 cells Gastric Homo sapiens (Human) CVCL_0434
NCI-H716 cells Colon Homo sapiens (Human) CVCL_1581
SNU-16 cells Gastric Homo sapiens (Human) CVCL_0076
NCI-H520 cells Lung Homo sapiens (Human) CVCL_1566
RT-4 cells Urinary bladder Homo sapiens (Human) CVCL_0036
ZR75-1 cells Breast Homo sapiens (Human) CVCL_0588
NCI-N87 cells Gastric Homo sapiens (Human) CVCL_1603
NCI-H716 cells Colon Homo sapiens (Human) CVCL_1581
KATO-3 cells Gastric Homo sapiens (Human) CVCL_0371
SNU-16 cells Gastric Homo sapiens (Human) CVCL_0076
NCI-H520 cells Lung Homo sapiens (Human) CVCL_1566
RT-4 cells Urinary bladder Homo sapiens (Human) CVCL_0036
UM-UC-14 cells Kidney Homo sapiens (Human) CVCL_2747
SUM-52PE cells Pleural effusion Homo sapiens (Human) CVCL_3425
NCI-H1581 cells Lung Homo sapiens (Human) CVCL_1479
MFE296 cells Endometrium Homo sapiens (Human) CVCL_1406
MFE280 cells Endometrium Homo sapiens (Human) CVCL_1405
KMS-11 cells Pleural effusion Homo sapiens (Human) CVCL_2989
HSC-39 cells Ascites Homo sapiens (Human) CVCL_A385
DMS-114 cells Lung Homo sapiens (Human) CVCL_1174
AN3 CA cells Endometrium Homo sapiens (Human) CVCL_0028
UM-UC-14 cells Kidney Homo sapiens (Human) CVCL_2747
KATO-III cells Pleural effusion Homo sapiens (Human) CVCL_0371
AN3 CA cells Endometrium Homo sapiens (Human) CVCL_0028
Experiment for
Molecule Alteration		 Microarray assay; Western blot analysis
Experiment for
Drug Resistance		 CCK-8 assay
Bladder cancer [ICD-11: 2C94]
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: Receptor tyrosine-protein kinase erbB-2 (ERBB2) [5]
Resistant Disease Bladder cancer [ICD-11: 2C94.0]
 Disease Info 
Molecule Alteration Missense mutation
p.S310F (c.929C>T)
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 3.09  Å
PDB: 3WLW
Mutant Type Structure Method: Electron microscopy Resolution: 3.09  Å
PDB: 7MN6
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.33
TM score: 0.96205
Amino acid change:
S310F
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
T
M
Q
E
V
L
C
A
T
A
G
L
T
C
D
R
M
W
10
|
K
G
L
L
R
L
L
L
P
A
A
L
S
L
P
P
E
P
T
G
20
|
H
A
L
A
D
S
M
T
L
Q
R
V
H
C
L
T
Y
G
Q
T
30
|
G
D
C
M
Q
K
V
L
V
R
Q
L
G
P
N
A
L
S
E
P
40
|
L
E
T
T
Y
H
L
L
P
D
T
M
N
L
A
R
S
H
L
L
50
|
S
Y
F
Q
L
G
Q
C
D
Q
I
V
Q
V
E
Q
V
G
Q
N
60
|
G
L
Y
E
V
L
L
T
I
Y
A
L
H
P
N
T
Q
N
V
A
70
|
R
S
Q
L
V
S
P
F
L
L
Q
Q
R
D
L
I
R
Q
I
E
80
|
V
V
R
Q
G
G
T
Y
Q
V
L
L
F
I
E
A
D
H
N
N
90
|
Y
Q
A
V
L
R
A
Q
V
V
L
P
D
L
N
Q
G
R
D
L
100
|
P
R
L
I
N
V
N
R
T
G
T
T
P
Q
V
L
T
F
G
E
110
|
A
D
S
N
P
Y
G
A
G
L
L
A
R
V
E
L
L
D
Q
N
120
|
L
G
R
D
S
P
L
L
T
N
E
N
I
T
L
T
K
P
G
V
130
|
G
T
V
G
L
A
I
S
Q
P
R
G
N
G
P
L
Q
R
L
E
140
|
C
L
Y
Q
Q
L
D
R
T
S
I
L
L
T
W
E
K
I
D
L
150
|
I
K
F
G
H
G
K
V
N
L
N
I
Q
Q
L
R
A
N
L
P
160
|
T
Q
L
L
I
C
D
Y
T
Q
N
D
R
T
S
I
R
L
A
W
170
|
C
K
H
D
P
I
C
F
S
H
P
K
M
N
C
N
K
Q
G
L
180
|
S
A
R
L
C
T
W
L
G
I
E
D
S
T
S
N
E
R
D
S
190
|
C
R
Q
A
S
C
L
H
T
P
R
C
T
S
V
P
C
M
A
C
200
|
G
K
G
G
C
S
A
R
R
C
C
W
K
G
G
E
P
S
L
S
210
|
P
E
T
D
D
C
C
Q
C
S
H
L
E
T
Q
R
C
T
A
V
220
|
A
C
G
A
C
G
T
G
G
C
P
A
K
R
H
C
S
K
D
G
230
|
C
P
L
L
A
P
C
T
L
D
H
C
F
C
N
H
H
E
S
Q
240
|
G
C
I
A
C
A
E
G
L
C
H
T
C
G
P
P
A
K
L
H
250
|
V
S
T
D
Y
C
N
L
T
A
D
C
T
L
F
H
E
F
S
N
260
|
M
H
P
S
N
G
P
I
E
C
G
E
R
L
Y
H
T
C
F
P
270
|
G
A
A
L
S
V
C
T
V
Y
T
N
A
T
C
D
P
T
Y
F
280
|
N
E
Y
S
L
M
S
P
T
N
D
P
V
E
G
G
S
R
C
Y
290
|
T
T
L
F
V
G
C
A
P
S
L
C
H
V
N
T
Q
A
E
C
300
|
V
P
T
Y
A
N
E
Y
D
L
G
S
T
T
Q
D
R
V
C
G
310
|
E
F
K
C
C
T
S
L
K
V
P
C
C
P
A
L
R
H
V
N
320
|
C
Q
Y
E
G
V
L
T
G
A
M
E
E
D
H
G
L
T
R
Q
330
|
E
R
V
C
R
E
A
K
V
C
T
S
S
K
A
P
N
C
I
A
340
|
Q
R
E
V
F
C
A
Y
G
G
C
L
K
G
K
M
I
E
F
H
350
|
G
L
S
R
L
E
A
V
F
R
L
A
P
V
E
T
S
S
F
A
360
|
D
N
G
I
D
Q
P
E
A
F
S
A
N
G
T
C
A
K
P
K
370
|
L
I
Q
F
P
G
E
S
Q
L
L
A
Q
F
V
L
F
P
E
E
380
|
T
S
L
F
E
D
E
G
I
D
T
P
G
A
Y
S
L
N
Y
T
390
|
I
A
S
P
A
L
W
Q
P
P
D
E
S
Q
L
L
P
Q
D
V
400
|
L
F
S
E
V
T
F
L
Q
E
N
E
L
I
Q
T
V
G
I
Y
410
|
R
L
G
Y
R
I
I
S
L
A
H
W
N
P
G
D
A
S
Y
L
420
|
S
P
L
D
T
L
L
S
Q
V
G
F
L
Q
G
N
I
L
S
Q
430
|
W
V
L
I
G
R
L
G
R
R
S
I
L
L
R
H
E
N
L
G
440
|
G
A
S
Y
G
S
L
L
A
T
L
L
I
Q
H
G
H
L
N
G
450
|
T
I
H
S
L
W
C
L
F
G
V
L
H
R
T
S
V
L
P
R
460
|
W
E
D
L
Q
G
L
S
F
G
R
L
N
A
P
L
H
I
Q
H
470
|
A
H
L
N
L
T
H
H
T
L
A
C
N
F
R
V
P
H
E
T
480
|
D
V
E
P
C
W
V
D
G
Q
E
L
G
F
L
R
A
N
C
P
490
|
H
H
Q
Q
L
A
C
L
A
L
R
H
G
T
H
A
C
N
W
R
500
|
G
P
P
E
G
D
P
E
T
C
Q
V
C
G
V
E
N
G
C
L
510
|
S
A
Q
C
F
H
L
Q
R
L
G
C
Q
A
E
R
C
G
V
H
520
|
E
C
E
W
C
G
R
P
V
G
L
P
Q
T
G
Q
L
C
P
V
530
|
R
N
E
C
Y
S
V
Q
N
F
A
L
R
R
H
G
C
Q
L
E
540
|
P
C
C
V
H
E
P
E
E
C
C
R
Q
V
P
L
Q
Q
N
G
550
|
G
L
S
P
V
R
T
E
C
Y
F
V
G
N
P
A
E
R
A
H
560
|
D
C
Q
L
C
P
V
C
A
H
-
P
-
E
-
C
-
Q
-
P
570
|
-
Q
-
N
-
G
-
S
-
V
-
T
-
C
-
F
-
G
-
P
580
|
-
E
-
A
-
D
-
Q
-
C
-
V
-
A
-
C
-
A
-
H
590
|
-
Y
-
K
-
D
-
P
-
P
-
F
-
C
-
V
-
A
-
R
600
|
-
C
-
P
-
S
-
G
-
V
-
K
-
P
-
D
-
L
-
S
610
|
-
Y
-
M
-
P
-
I
-
W
-
K
-
F
-
P
-
D
-
E
620
|
-
E
-
G
-
A
-
C
-
Q
-
P
-
C
-
P
-
I
-
N
630
|
-
C
-
T
-
H
-
S
-
C
-
V
-
D
-
L
-
D
-
D
640
|
-
K
-
G
-
C
-
P
-
A
-
E
-
Q
-
R
-
A
-
S
650
|
-
P
-
L
-
T
-
S
-
I
-
I
-
S
-
A
-
V
-
V
660
|
-
G
-
I
-
L
-
L
-
V
-
V
-
V
-
L
-
G
-
V
670
|
-
V
-
F
-
G
-
I
-
L
-
I
-
K
-
R
-
R
-
Q
680
|
-
Q
-
K
-
I
-
R
-
K
-
Y
-
T
-
M
-
R
-
R
690
|
-
L
-
L
-
Q
-
E
-
T
-
E
-
L
-
V
-
E
-
P
700
|
-
L
-
T
-
P
-
S
-
G
-
A
-
M
-
P
-
N
-
Q
710
|
-
A
-
Q
-
M
-
R
-
I
-
L
-
K
-
E
-
T
-
E
720
|
-
L
-
R
-
K
-
V
-
K
-
V
-
L
-
G
-
S
-
G
730
|
-
A
-
F
-
G
-
T
-
V
-
Y
-
K
-
G
-
I
-
W
740
|
-
I
-
P
-
D
-
G
-
E
-
N
-
V
-
K
-
I
-
P
750
|
-
V
-
A
-
I
-
K
-
V
-
L
-
R
-
E
-
N
-
T
760
|
-
S
-
P
-
K
-
A
-
N
-
K
-
E
-
I
-
L
-
D
770
|
-
E
-
A
-
Y
-
V
-
M
-
A
-
G
-
V
-
D
-
S
780
|
-
P
-
Y
-
V
-
S
-
R
-
L
-
L
-
G
-
I
-
C
790
|
-
L
-
T
-
S
-
T
-
V
-
Q
-
L
-
V
-
T
-
Q
800
|
-
L
-
M
-
P
-
Y
-
G
-
C
-
L
-
L
-
D
-
H
810
|
-
V
-
R
-
E
-
N
-
R
-
G
-
R
-
L
-
G
-
S
820
|
-
Q
-
D
-
L
-
L
-
N
-
W
-
C
-
M
-
Q
-
I
830
|
-
A
-
K
-
G
-
M
-
S
-
Y
-
L
-
E
-
D
-
V
840
|
-
R
-
L
-
V
-
H
-
R
-
D
-
L
-
A
-
A
-
R
850
|
-
N
-
V
-
L
-
V
-
K
-
S
-
P
-
N
-
H
-
V
860
|
-
K
-
I
-
T
-
D
-
F
-
G
-
L
-
A
-
R
-
L
870
|
-
L
-
D
-
I
-
D
-
E
-
T
-
E
-
Y
-
H
-
A
880
|
-
D
-
G
-
G
-
K
-
V
-
P
-
I
-
K
-
W
-
M
890
|
-
A
-
L
-
E
-
S
-
I
-
L
-
R
-
R
-
R
-
F
900
|
-
T
-
H
-
Q
-
S
-
D
-
V
-
W
-
S
-
Y
-
G
910
|
-
V
-
T
-
V
-
W
-
E
-
L
-
M
-
T
-
F
-
G
920
|
-
A
-
K
-
P
-
Y
-
D
-
G
-
I
-
P
-
A
-
R
930
|
-
E
-
I
-
P
-
D
-
L
-
L
-
E
-
K
-
G
-
E
940
|
-
R
-
L
-
P
-
Q
-
P
-
P
-
I
-
C
-
T
-
I
950
|
-
D
-
V
-
Y
-
M
-
I
-
M
-
V
-
K
-
C
-
W
960
|
-
M
-
I
-
D
-
S
-
E
-
C
-
R
-
P
-
R
-
F
970
|
-
R
-
E
-
L
-
V
-
S
-
E
-
F
-
S
-
R
-
M
980
|
-
A
-
R
-
D
-
P
-
Q
-
R
-
F
-
V
-
V
-
I
990
|
-
Q
-
N
-
E
-
D
-
L
-
G
-
P
-
A
-
S
-
P
1000
|
-
L
-
D
-
S
-
T
-
F
-
Y
-
R
-
S
-
L
-
L
1010
|
-
E
-
D
-
D
-
D
-
M
-
G
-
D
-
L
-
V
-
D
1020
|
-
A
-
E
-
E
-
Y
-
L
-
V
-
P
-
Q
-
Q
-
G
1030
|
-
G
-
G
-
S
-
L
-
E
-
V
-
L
-
F
-
Q
-
G
1040
|
-
P
-
S
-
S
-
P
-
S
-
G
-
S
-
S
-
M
-
K
1050
|
-
I
-
E
-
E
-
G
-
K
-
L
-
V
-
I
-
W
-
I
1060
|
-
N
-
G
-
D
-
K
-
G
-
Y
-
N
-
G
-
L
-
A
1070
|
-
E
-
V
-
G
-
K
-
K
-
F
-
E
-
K
-
D
-
T
1080
|
-
G
-
I
-
K
-
V
-
T
-
V
-
E
-
H
-
P
-
D
1090
|
-
K
-
L
-
E
-
E
-
K
-
F
-
P
-
Q
-
V
-
A
1100
|
-
A
-
T
-
G
-
D
-
G
-
P
-
D
-
I
-
I
-
F
1110
|
-
W
-
A
-
H
-
D
-
R
-
F
-
G
-
G
-
Y
-
A
1120
|
-
Q
-
S
-
G
-
L
-
L
-
A
-
E
-
I
-
T
-
P
1130
|
-
D
-
K
-
A
-
F
-
Q
-
D
-
K
-
L
-
Y
-
P
1140
|
-
F
-
T
-
W
-
D
-
A
-
V
-
R
-
Y
-
N
-
G
1150
|
-
K
-
L
-
I
-
A
-
Y
-
P
-
I
-
A
-
V
-
E
1160
|
-
A
-
L
-
S
-
L
-
I
-
Y
-
N
-
K
-
D
-
L
1170
|
-
L
-
P
-
N
-
P
-
P
-
K
-
T
-
W
-
E
-
E
1180
|
-
I
-
P
-
A
-
L
-
D
-
K
-
E
-
L
-
K
-
A
1190
|
-
K
-
G
-
K
-
S
-
A
-
L
-
M
-
F
-
N
-
L
1200
|
-
Q
-
E
-
P
-
Y
-
F
-
T
-
W
-
P
-
L
-
I
1210
|
-
A
-
A
-
D
-
G
-
G
-
Y
-
A
-
F
-
K
-
Y
1220
|
-
E
-
N
-
G
-
K
-
Y
-
D
-
I
-
K
-
D
-
V
1230
|
-
G
-
V
-
D
-
N
-
A
-
G
-
A
-
K
-
A
-
G
1240
|
-
L
-
T
-
F
-
L
-
V
-
D
-
L
-
I
-
K
-
N
1250
|
-
K
-
H
-
M
-
N
-
A
-
D
-
T
-
D
-
Y
-
S
1260
|
-
I
-
A
-
E
-
A
-
A
-
F
-
N
-
K
-
G
-
E
1270
|
-
T
-
A
-
M
-
T
-
I
-
N
-
G
-
P
-
W
-
A
1280
|
-
W
-
S
-
N
-
I
-
D
-
T
-
S
-
K
-
V
-
N
1290
|
-
Y
-
G
-
V
-
T
-
V
-
L
-
P
-
T
-
F
-
K
1300
|
-
G
-
Q
-
P
-
S
-
K
-
P
-
F
-
V
-
G
-
V
1310
|
-
L
-
S
-
A
-
G
-
I
-
N
-
A
-
A
-
S
-
P
1320
|
-
N
-
K
-
E
-
L
-
A
-
K
-
E
-
F
-
L
-
E
1330
|
-
N
-
Y
-
L
-
L
-
T
-
D
-
E
-
G
-
L
-
E
1340
|
-
A
-
V
-
N
-
K
-
D
-
K
-
P
-
L
-
G
-
A
1350
|
-
V
-
A
-
L
-
K
-
S
-
Y
-
E
-
E
-
E
-
L
1360
|
-
A
-
K
-
D
-
P
-
R
-
I
-
A
-
A
-
T
-
M
1370
|
-
E
-
N
-
A
-
Q
-
K
-
G
-
E
-
I
-
M
-
P
1380
|
-
N
-
I
-
P
-
Q
-
M
-
S
-
A
-
F
-
W
-
Y
1390
|
-
A
-
V
-
R
-
T
-
A
-
V
-
I
-
N
-
A
-
A
1400
|
-
S
-
G
-
R
-
Q
-
T
-
V
-
D
-
E
-
A
-
L
1410
|
-
K
-
D
-
A
-
Q
-
T
-
N
-
S
-
S
-
S
-
S
1420
|
-
G
-
P
-
S
-
S
-
P
-
S
-
A
-
W
-
S
-
H
1430
|
-
P
-
Q
-
F
-
E
-
K
-
G
-
G
-
G
-
S
-
G
1440
|
-
G
-
G
-
S
-
G
-
G
-
S
-
S
-
A
-
W
-
S
1450
|
-
H
-
P
-
Q
-
F
-
E
-
K
Click to Show/Hide the Structure
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model 5637 cells Bladder Homo sapiens (Human) CVCL_0126
J82 cells Bladder Homo sapiens (Human) CVCL_0359
RT4 cells Bladder Homo sapiens (Human) CVCL_0036
T24 cells Bladder Homo sapiens (Human) CVCL_0554
SW780 cells Bladder Homo sapiens (Human) CVCL_1728
HT1376 cells Bladder Homo sapiens (Human) CVCL_1292
RT112 cells Bladder Homo sapiens (Human) CVCL_1670
TCCSuP cells Bladder Homo sapiens (Human) CVCL_1738
UM-UC3 cells Urinary bladder Homo sapiens (Human) CVCL_1783
WH cells Bladder Homo sapiens (Human) CVCL_0C39
VM-CUBIII cells Urinary bladder Homo sapiens (Human) CVCL_9830
VM-CUBII cells Urinary bladder Homo sapiens (Human) CVCL_9829
VM-CUBI cells Obturator lymph node Homo sapiens (Human) CVCL_1786
UM-UC-14 cells Kidney Homo sapiens (Human) CVCL_2747
TSU-PR1 cells Urinary bladder Homo sapiens (Human) CVCL_4014
SW1710 cells Bladder Homo sapiens (Human) CVCL_1721
SD cells Bladder Homo sapiens (Human) CVCL_W902
KU-19 cells Blood Bos taurus (Bovine) CVCL_VN09
JO'N cells Urinary bladder Homo sapiens (Human) CVCL_M891
JMSU-1 cells Ascites Homo sapiens (Human) CVCL_2081
HT1197 cells Urinary bladder Homo sapiens (Human) CVCL_1291
DSH1 cells Urinary bladder Homo sapiens (Human) CVCL_1182
CAL-29 cells Urinary bladder Homo sapiens (Human) CVCL_1808
BFTC-905 cells Urinary bladder Homo sapiens (Human) CVCL_1083
BC-3C cells Urinary bladder Homo sapiens (Human) CVCL_1958
97-7 cells Bladder Homo sapiens (Human) CVCL_8625
97-24 cells Bladder Homo sapiens (Human) CVCL_8621
97-18 cells Bladder Homo sapiens (Human) CVCL_8619
97-1 cells Bladder Homo sapiens (Human) CVCL_8616
96-1 cells Bladder Homo sapiens (Human) CVCL_8609
94-10 cells Bladder Homo sapiens (Human) CVCL_8608
647V cells Urinary bladder Homo sapiens (Human) CVCL_1049
253J cells Lymph node Homo sapiens (Human) CVCL_7935/CVCL_7938
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 MTT assay
Uveal melanoma [ICD-11: 2D0Y]
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: Guanine nucleotide-binding protein alpha-q (GNAQ) [14]
Sensitive Disease Uveal melanoma [ICD-11: 2D0Y.0]
 Disease Info 
Molecule Alteration Missense mutation
p.Q209L (c.626A>T)
 Molecule Info 
Wild Type Structure Method: Electron microscopy Resolution: 3.50  Å
PDB: 6VU5
Mutant Type Structure Method: Electron microscopy Resolution: 2.90  Å
PDB: 7F6G
   Download The Information of Sequence       Download The Structure File   
RMSD: 1.91
TM score: 0.72705
Amino acid change:
Q209L
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
-
M
-
H
-
H
-
H
-
H
-
H
-
H
-
H
-
H
0
|
-
H
M
H
T
T
L
L
E
E
S
S
I
I
M
M
A
A
C
C
10
|
C
C
L
L
S
S
E
E
E
E
A
A
K
K
E
E
A
A
R
R
20
|
R
R
I
I
N
N
D
D
E
E
I
I
E
E
R
R
Q
Q
L
L
30
|
R
R
R
R
D
D
K
K
R
R
D
D
A
A
R
R
R
R
E
E
40
|
L
L
K
K
L
L
L
L
L
L
L
L
G
G
T
T
G
G
E
E
50
|
S
S
G
G
K
K
S
S
T
T
F
F
I
I
K
K
Q
Q
M
M
60
|
R
R
I
I
I
I
H
H
G
G
S
S
G
G
Y
Y
S
S
D
D
70
|
E
E
D
D
K
K
R
R
G
G
F
F
T
T
K
K
L
L
V
V
80
|
Y
Y
Q
Q
N
N
I
I
F
F
T
T
A
A
M
M
Q
Q
A
A
90
|
M
M
I
I
R
R
A
A
M
M
D
D
T
T
L
L
K
K
I
I
100
|
P
P
Y
Y
K
K
Y
Y
E
E
H
H
N
N
K
K
A
A
H
H
110
|
A
A
Q
Q
L
L
V
V
R
R
E
E
V
V
D
D
V
V
E
E
120
|
K
K
V
V
S
S
A
A
F
F
E
E
N
N
P
P
Y
Y
V
V
130
|
D
D
A
A
I
I
K
K
S
S
L
L
W
W
N
N
D
D
P
P
140
|
G
G
I
I
Q
Q
E
E
C
C
Y
Y
D
D
R
R
R
R
R
R
150
|
E
E
Y
Y
Q
Q
L
L
S
S
D
D
S
S
T
T
K
K
Y
Y
160
|
Y
Y
L
L
N
N
D
D
L
L
D
D
R
R
V
V
A
A
D
D
170
|
P
P
A
A
Y
Y
L
L
P
P
T
T
Q
Q
Q
Q
D
D
V
V
180
|
L
L
R
R
V
V
R
Q
V
V
P
P
T
T
T
T
G
G
I
I
190
|
I
I
E
E
Y
Y
P
P
F
F
D
D
L
L
Q
Q
S
S
V
V
200
|
I
I
F
F
R
R
M
M
V
V
D
D
V
V
G
G
G
G
Q
L
210
|
R
R
S
S
E
E
R
R
R
R
K
K
W
W
I
I
H
H
C
C
220
|
F
F
E
E
N
N
V
V
T
T
S
S
I
I
M
M
F
F
L
L
230
|
V
V
A
A
L
L
S
S
E
E
Y
Y
D
D
Q
Q
V
V
L
L
240
|
V
V
E
E
S
S
D
D
N
N
E
E
N
N
R
R
M
M
E
E
250
|
E
E
S
S
K
K
A
A
L
L
F
F
R
R
T
T
I
I
I
I
260
|
T
T
Y
Y
P
P
W
W
F
F
Q
Q
N
N
S
S
S
S
V
V
270
|
I
I
L
L
F
F
L
L
N
N
K
K
K
K
D
D
L
L
L
L
280
|
E
E
E
E
K
K
I
I
M
M
Y
Y
S
S
H
H
L
L
V
V
290
|
D
D
Y
Y
F
F
P
P
E
E
Y
Y
D
D
G
G
P
P
Q
Q
300
|
R
R
D
D
A
A
Q
Q
A
A
A
A
R
R
E
E
F
F
I
I
310
|
L
L
K
K
M
M
F
F
V
V
D
D
L
L
N
N
P
P
D
D
320
|
S
S
D
D
K
K
I
I
I
I
Y
Y
S
S
H
H
F
F
T
T
330
|
C
C
A
A
T
T
D
D
T
T
E
E
N
N
I
I
R
R
F
F
340
|
V
V
F
F
A
A
A
A
V
V
K
K
D
D
T
T
I
I
L
L
350
|
Q
Q
L
L
N
N
L
L
K
K
E
E
Y
Y
N
N
L
L
V
V
Click to Show/Hide the Structure
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model Omm13 cells N.A. N.A. N.A.
Mel270 cells Skin Homo sapiens (Human) CVCL_C302
Mel202 cells Eye Homo sapiens (Human) CVCL_C301
Experiment for
Molecule Alteration		 Immunoblotting analysis
Experiment for
Drug Resistance		 CCK-8 assay
Mechanism Description The missense mutation p.Q209L (c.626A>T) in gene GNAQ cause the sensitivity of Selumetinib by unusual activation of pro-survival pathway
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: Serine/threonine-protein kinase B-raf (BRAF) [15]
Sensitive Disease Thyroid gland cancer [ICD-11: 2D10.0]
 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
-
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 A375 cells Skin Homo sapiens (Human) CVCL_0132
BCPAP cells Thyroid Homo sapiens (Human) CVCL_0153
SW1736 cells Thyroid Homo sapiens (Human) CVCL_3883
C643 cells Thyroid gland Homo sapiens (Human) CVCL_5969
CAL62 cells Thyroid gland Homo sapiens (Human) CVCL_1112
In Vivo Model Athymic nude mouse PDX xenografts model Mus musculus
Experiment for
Molecule Alteration		 Immunoblotting assay; Immunoprecipitation assy
Experiment for
Drug Resistance		 SRB staining assay; Promega assay
Mechanism Description Activation of the Mitogen Activated Protein (MAP) Kinase pathway was increased in all four of the dasatinib-resistant cell lines, likely due to B-Raf and c-Raf dimerization. Furthermore, MAP2K1/MAP2K2 (MEK1/2) inhibition restored sensitivity in all four of the dasatinib-resistant cell lines, and overcome acquired resistance to dasatinib in the RAS-mutant Cal62 cell line, in vivo. Together, these studies demonstrate that acquisition of the c-Src gatekeeper mutation and MAP Kinase pathway signaling play important roles in promoting resistance to the Src inhibitor, dasatinib.
References
Ref 1 Inhibition of RAF Isoforms and Active Dimers by LY3009120 Leads to Anti-tumor Activities in RAS or BRAF Mutant CancersCancer Cell. 2015 Sep 14;28(3):384-98. doi: 10.1016/j.ccell.2015.08.002. Epub 2015 Sep 3.
Ref 2 Phase II study of the oral MEK inhibitor selumetinib in advanced acute myelogenous leukemia: a University of Chicago phase II consortium trialClin Cancer Res. 2014 Jan 15;20(2):490-8. doi: 10.1158/1078-0432.CCR-13-1311. Epub 2013 Oct 31.
Ref 3 Regulation of MEK inhibitor selumetinib sensitivity by AKT phosphorylation in the novel BRAF L525R mutant. Int J Clin Oncol. 2023 May;28(5):654-663.
Ref 4 Establishment of prognostic risk model and drug sensitivity based on prognostic related genes of esophageal cancer. Sci Rep. 2022 May 14;12(1):8008.
Ref 5 Impact of ERBB2 mutations on in vitro sensitivity of bladder cancer to lapatinibCancer Biol Ther. 2014 Sep;15(9):1239-47. doi: 10.4161/cbt.29687. Epub 2014 Jul 14.
Ref 6 ERK Signal Suppression and Sensitivity to CH5183284/Debio 1347, a Selective FGFR InhibitorMol Cancer Ther. 2015 Dec;14(12):2831-9. doi: 10.1158/1535-7163.MCT-15-0497. Epub 2015 Oct 5.
Ref 7 Antitumor activity of selective MEK1/2 inhibitor AZD6244 in combination with PI3K/mTOR inhibitor BEZ235 in gefitinib-resistant NSCLC xenograft modelsJ Exp Clin Cancer Res. 2014 Jun 17;33(1):52. doi: 10.1186/1756-9966-33-52.
Ref 8 Increase in constitutively active MEK1 species by introduction of MEK1 mutations identified in cancersBiochim Biophys Acta Proteins Proteom. 2019 Jan;1867(1):62-70. doi: 10.1016/j.bbapap.2018.05.004. Epub 2018 May 9.
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 Characteristics of lung cancers harboring NRAS mutationsClin Cancer Res. 2013 May 1;19(9):2584-91. doi: 10.1158/1078-0432.CCR-12-3173. Epub 2013 Mar 20.
Ref 11 Reversing melanoma cross-resistance to BRAF and MEK inhibitors by co-targeting the AKT/mTOR pathwayPLoS One. 2011;6(12):e28973. doi: 10.1371/journal.pone.0028973. Epub 2011 Dec 14.
Ref 12 Phase I pharmacokinetic and pharmacodynamic study of the oral, small-molecule mitogen-activated protein kinase kinase 1/2 inhibitor AZD6244 (ARRY-142886) in patients with advanced cancersJ Clin Oncol. 2008 May 1;26(13):2139-46. doi: 10.1200/JCO.2007.14.4956. Epub 2008 Apr 7.
Ref 13 Turk J Haematol. 2016 Mar 5;33(1):41-7. doi: 10.4274/tjh.2014.0010. Epub 2014 May 21.
Ref 14 Identification of unique MEK-dependent genes in GNAQ mutant uveal melanoma involved in cell growth, tumor cell invasion, and MEK resistanceClin Cancer Res. 2012 Jul 1;18(13):3552-61. doi: 10.1158/1078-0432.CCR-11-3086. Epub 2012 May 1.
Ref 15 The Mitogen-Activated Protein Kinase Pathway Facilitates Resistance to the Src Inhibitor Dasatinib in Thyroid CancerMol Cancer Ther. 2016 Aug;15(8):1952-63. doi: 10.1158/1535-7163.MCT-15-0702. Epub 2016 May 24.

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