Drug Information

Drug (ID: DG01566) and It's Reported Resistant Information
Name
Refametinib
Synonyms
Refametinib; 923032-37-5; RDEA119; RDEA 119; BAY 869766; UNII-JPX07AFM0N; (S)-N-(3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide; JPX07AFM0N; Refametinib (RDEA119); BAY-869766; BAY 8697661; Refametinib (RDEA119, Bay 86-9766); N-[3,4-difluoro-2-(2-fluoro-4-iodoanilino)-6-methoxyphenyl]-1-[(2S)-2,3-dihydroxypropyl]cyclopropane-1-sulfonamide; Refametinib R enantiomer; Refametinib [INN]; BAY 86-9766; RDEA-119; 3e8n; BAY 86-97661; Refametinib; RDEA119; SCHEMBL345333; C19H20F3IN2O5S; GTPL7942; Refametinib (BAY86-9766); CHEMBL1236682; DTXSID40238961; BDBM520650; 923032-38-6; AOB87134; EX-A2481; 2254AH; MFCD18633256; NSC800864; s1089; ZINC39187987; AKOS025401896; BAY86-9766; CCG-270103; CS-1818; DB06309; NSC-800864; BAY 86-9766;RDEA119; BAY-86-9766; BAY-8697661; NCGC00188380-01; NCGC00188380-02; NCGC00188380-03; AC-26962; AS-16994; Cyclopropanesulfonamide, N-(3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-6-methoxyphenyl)-1-((2S)-2,3-dihydroxypropyl)-; HY-14691; SW218136-2; J3.661.482J; F51934; US11147816, Refametinib (RDEA119, Bay; Q27088526; BAY 869766;BAY 86-97661;RDEA-119;RDEA119; (S)-N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide; 923032-36-4; N-{3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]-6-methoxyphenyl}-1-[(2S)-2,3-dihydroxypropyl]cyclopropanesulfonamide; RDEA-119 S enantiomer; ; ; BAY-86-9766 S enantiomer; ; ; N-[3,4-Difluoro-2-(2-fluoro-4-iodoanilino)-6-methoxyphenyl]-1-[(2S)-2,3-dihydroxypropyl]cyclopropane-1-sulfonamide; VRA
    Click to Show/Hide
Indication
In total 1 Indication(s)
Thrombosis [ICD-11: DB61-GB90]
Phase 3
[1]
Structure
Drug Resistance Disease(s)
Disease(s) with Resistance Information Validated by in-vivo Model for This Drug (1 diseases)
Esophageal cancer [ICD-11: 2B70]
[2]
Disease(s) with Clinically Reported Resistance for This Drug (1 diseases)
Melanoma [ICD-11: 2C30]
[4]
Target PI3-kinase beta (PIK3CB) PK3CB_HUMAN [4]
Click to Show/Hide the Molecular Information and External Link(s) of This Drug
Formula
9
IsoSMILES
COC1=CC(=C(C(=C1NS(=O)(=O)C2(CC2)C[C@@H](CO)O)NC3=C(C=C(C=C3)I)F)F)F
InChI
InChI=1S/C19H20F3IN2O5S/c1-30-15-7-13(21)16(22)18(24-14-3-2-10(23)6-12(14)20)17(15)25-31(28,29)19(4-5-19)8-11(27)9-26/h2-3,6-7,11,24-27H,4-5,8-9H2,1H3/t11-/m0/s1
InChIKey
RDSACQWTXKSHJT-NSHDSACASA-N
PubChem CID
44182295
TTD Drug ID
D0D0QA
VARIDT ID
DR1879
DrugBank ID
DB06309
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
Colorectal cancer [ICD-11: 2B91]
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) [5]
Sensitive 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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510
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570
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590
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600
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610
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630
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640
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Y
Y
A
A
F
F
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E
E
L
L
650
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M
M
T
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Y
Y
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S
N
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I
660
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N
N
N
N
R
R
D
D
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I
I
I
I
F
F
M
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670
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G
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R
R
G
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Y
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P
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D
D
L
L
S
S
680
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K
K
V
V
R
R
S
S
N
N
C
C
P
P
K
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A
A
M
M
690
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K
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R
R
L
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A
A
E
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C
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700
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710
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720
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Click to Show/Hide the Structure
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model MDA-MB-231 cells Breast Homo sapiens (Human) CVCL_0062
A375 cells Skin Homo sapiens (Human) CVCL_0132
HT-29 cells Colon Homo sapiens (Human) CVCL_0320
A431 cells Skin Homo sapiens (Human) CVCL_0037
COLO205 cells Colon Homo sapiens (Human) CVCL_F402
BxPc3 cells Pancreas Homo sapiens (Human) CVCL_0186
SkMEL28 cells Skin Homo sapiens (Human) CVCL_0526
In Vivo Model Female athymic nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Biochemical kinase assays
Experiment for
Drug Resistance		 CellTiter 96 Aqueous One assay
Mechanism Description The missense mutation p.V600E (c.1799T>A) in gene BRAF cause the sensitivity of Refametinib 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: Serine/threonine-protein kinase B-raf (BRAF) [5]
Sensitive Disease Melanoma [ICD-11: 2C30.0]
 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
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M
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500
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520
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570
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S
S
I
I
I
I
H
H
R
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580
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N
N
N
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F
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590
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610
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F
F
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L
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G
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S
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W
620
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M
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A
P
P
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E
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D
630
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N
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Y
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640
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F
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650
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P
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660
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N
N
N
N
R
R
D
D
Q
Q
I
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I
I
F
F
M
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V
670
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G
G
R
R
G
G
Y
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P
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D
L
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S
680
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K
K
V
V
R
R
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S
N
N
C
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P
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K
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A
A
M
M
690
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K
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R
R
L
L
M
M
A
A
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E
C
C
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700
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K
R
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710
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720
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R
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Click to Show/Hide the Structure
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model MDA-MB-231 cells Breast Homo sapiens (Human) CVCL_0062
A375 cells Skin Homo sapiens (Human) CVCL_0132
HT-29 cells Colon Homo sapiens (Human) CVCL_0320
A431 cells Skin Homo sapiens (Human) CVCL_0037
COLO205 cells Colon Homo sapiens (Human) CVCL_F402
BxPc3 cells Pancreas Homo sapiens (Human) CVCL_0186
SkMEL28 cells Skin Homo sapiens (Human) CVCL_0526
In Vivo Model Female athymic nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Biochemical kinase assays
Experiment for
Drug Resistance		 CellTiter 96 Aqueous One assay
Mechanism Description The missense mutation p.V600E (c.1799T>A) in gene BRAF cause the sensitivity of Refametinib by unusual activation of pro-survival pathway
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) [4]
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
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A
A
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C
10
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E
E
E
A
A
K
K
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E
A
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20
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30
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R
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A
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E
40
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L
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50
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M
60
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Y
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70
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E
E
D
D
K
K
R
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G
G
F
F
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T
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L
V
V
80
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Y
Y
Q
Q
N
N
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I
F
F
T
T
A
A
M
M
Q
Q
A
A
90
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M
M
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I
R
R
A
A
M
M
D
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T
L
L
K
K
I
I
100
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P
P
Y
Y
K
K
Y
Y
E
E
H
H
N
N
K
K
A
A
H
H
110
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A
A
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L
L
V
V
R
R
E
E
V
V
D
D
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V
E
E
120
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K
K
V
V
S
S
A
A
F
F
E
E
N
N
P
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Y
Y
V
V
130
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D
D
A
A
I
I
K
K
S
S
L
L
W
W
N
N
D
D
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P
140
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G
G
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I
Q
Q
E
E
C
C
Y
Y
D
D
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R
R
R
R
150
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E
E
Y
Y
Q
Q
L
L
S
S
D
D
S
S
T
T
K
K
Y
Y
160
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Y
Y
L
L
N
N
D
D
L
L
D
D
R
R
V
V
A
A
D
D
170
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P
P
A
A
Y
Y
L
L
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P
T
T
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Q
Q
Q
D
D
V
V
180
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L
L
R
R
V
V
R
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V
P
P
T
T
T
T
G
G
I
I
190
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I
I
E
E
Y
Y
P
P
F
F
D
D
L
L
Q
Q
S
S
V
V
200
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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
Mechanism Description The missense mutation p.Q209L (c.626A>T) in gene GNAQ cause the sensitivity of Refametinib by aberration of the drug's therapeutic target
References
Ref 1 Identification of an "Exceptional Responder" Cell Line to MEK1 Inhibition: Clinical Implications for MEK-Targeted TherapyMol Cancer Res. 2016 Feb;14(2):207-15. doi: 10.1158/1541-7786.MCR-15-0321. Epub 2015 Nov 18.
Ref 2 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 3 Establishment of prognosis model of hepatocellular carcinoma based on prognosis related gene analysis and study on gene regulation mechanism of model. Heliyon. 2024 Sep 30;10(21):e38729.
Ref 4 Multicenter phase I trial of the mitogen-activated protein kinase 1/2 inhibitor BAY 86-9766 in patients with advanced cancerClin Cancer Res. 2013 Mar 1;19(5):1232-43. doi: 10.1158/1078-0432.CCR-12-3529. Epub 2013 Feb 22.
Ref 5 RDEA119/BAY 869766: a potent, selective, allosteric inhibitor of MEK1/2 for the treatment of cancerCancer Res. 2009 Sep 1;69(17):6839-47. doi: 10.1158/0008-5472.CAN-09-0679. Epub 2009 Aug 25.

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