Drug Information

Drug (ID: DG01538) and It's Reported Resistant Information
Name
PLX4720
Synonyms
PLX-4720; 918505-84-7; PLX4720; N-(3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide; PLX 4720; N-[3-[(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)carbonyl]-2,4-difluorophenyl]-1-propanesulfonamide; UNII-EQY31RO8HA; N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl]propane-1-sulfonamide; EQY31RO8HA; CHEBI:90295; N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]propane-1-sulfonamide; N-{3-[(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)carbonyl]-2,4-difluorophenyl}propane-1-sulfonamide; C17H14ClF2N3O3S; N-[3-({5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl}carbonyl)-2,4-difluorophenyl]propane-1-sulfonamide; a,a-dimethoxytoluene; 3c4c; MLS006010065; SCHEMBL133733; GTPL5703; CHEMBL1230020; BDBM25617; AMY2871; DTXSID10238711; EX-A186; SYN1069; HMS3244C03; HMS3244C04; HMS3244D03; HMS3265I09; HMS3265I10; HMS3265J09; HMS3265J10; HMS3654M10; HMS3750K11; HMS3884C05; ACT06829; AOB87700; BCP01754; PLX-4720,PLX4720; BBL102256; MFCD14635203; NSC757438; s1152; STL556055; ZINC39059267; AKOS015919071; CCG-268810; CS-0094; DB06999; NSC-757438; NCGC00187911-01; NCGC00187911-02; NCGC00187911-06; 1-Propanesulfonamide, N-[3-[(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)carbonyl]-2,4-difluorophenyl]-; AC-23171; AS-19376; HY-51424; SMR004701225; DB-003736; FT-0673969; SW218119-2; X7406; A19411; Raf Kinase Inhibitor V - CAS 918505-84-7; 505P847; J-522979; BRD-K16478699-001-01-9; Q27088418; N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]pr opane-1-sulfonamide; propane-1-sulfonic acid [3-(5-chloro-1h-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide; Propane-1-sulfonic acid[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl]-amide
    Click to Show/Hide
Indication
In total 4 Indication(s)
Ovarian cancer [ICD-11: 2C73]
Phase 1
[1]
Ovarian cancer [ICD-11: 2C73]
Phase 1
[1]
Pancreatic cancer [ICD-11: 2C10]
Phase 1
[1]
Prostate cancer [ICD-11: 2C82]
Phase 1
[1]
Structure
Drug Resistance Disease(s)
Disease(s) with Clinically Reported Resistance for This Drug (2 diseases)
Brain cancer [ICD-11: 2A00]
[2]
Melanoma [ICD-11: 2C30]
[3]
Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (1 diseases)
Melanoma [ICD-11: 2C30]
[4]
Target Poly [ADP-ribose] polymerase (PARP) NOUNIPROTAC [5]
Click to Show/Hide the Molecular Information and External Link(s) of This Drug
Formula
6
IsoSMILES
CCCS(=O)(=O)NC1=C(C(=C(C=C1)F)C(=O)C2=CNC3=C2C=C(C=N3)Cl)F
InChI
InChI=1S/C17H14ClF2N3O3S/c1-2-5-27(25,26)23-13-4-3-12(19)14(15(13)20)16(24)11-8-22-17-10(11)6-9(18)7-21-17/h3-4,6-8,23H,2,5H2,1H3,(H,21,22)
InChIKey
YZDJQTHVDDOVHR-UHFFFAOYSA-N
PubChem CID
24180719
ChEBI ID
CHEBI:90295
TTD Drug ID
D0J9HW
DrugBank ID
DB06999
Type(s) of Resistant Mechanism of This Drug
  ADTT: Aberration of the Drug's Therapeutic Target
  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 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 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
In Vitro Model GBM cells Brain Homo sapiens (Human) N.A.
In Vivo Model Athymic mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 qPCR
Experiment for
Drug Resistance		 Alamar blue proliferation assay
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [6]
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
In Vitro Model LN229 cells Brain Homo sapiens (Human) CVCL_0393
A172 cells Brain Homo sapiens (Human) CVCL_0131
U87 cells Brain Homo sapiens (Human) CVCL_0022
SNB19 cells Brain Homo sapiens (Human) CVCL_0535
U138 cells Brain Homo sapiens (Human) CVCL_0020
T98G cells Brain Homo sapiens (Human) CVCL_0556
HS683 cells Brain Homo sapiens (Human) CVCL_0844
DBTRG-05MG cells Brain Homo sapiens (Human) CVCL_1169
NMC-G1 cells Brain Homo sapiens (Human) CVCL_1608
MO59J cells Brain Homo sapiens (Human) CVCL_0400
LN405 cells Brain Homo sapiens (Human) CVCL_1378
LN172 cells N.A. N.A. N.A.
KG1c cells Brain Homo sapiens (Human) CVCL_2971
H4 cells Brain Homo sapiens (Human) CVCL_1239
GMS10 cells Brain Homo sapiens (Human) CVCL_1233
GAMG cells Brain Homo sapiens (Human) CVCL_1226
CCF-STTG1 cells Brain Homo sapiens (Human) CVCL_1118
AM-38 cells Brain Homo sapiens (Human) CVCL_1070
8MGBA cells Brain Homo sapiens (Human) CVCL_1052
42MGBA cells Brain Homo sapiens (Human) CVCL_1798
In Vivo Model BALB/c nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 CCK-8 assay
Mechanism Description PLX4720 suppresses MEK-ERK phosphorylation and cell proliferation in MA cells containing BRAFV600E mutation.
Solid tumour/cancer [ICD-11: 2A00-2F9Z]
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [7]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
 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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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
In Vitro Model HEK293 cells Kidney Homo sapiens (Human) CVCL_0045
Ba/F3 cells Colon Homo sapiens (Human) CVCL_0161
In Vivo Model Nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 BRAF kinase assay
Experiment for
Drug Resistance		 Flow cytometry assay
Mechanism Description The missense mutation p.V600E (c.1799T>A) in gene BRAF cause the sensitivity of PLX4720 by aberration of the drug's therapeutic target
  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
-
20
|
M
-
A
-
H
-
H
-
H
-
H
-
H
-
H
-
A
-
A
-
30
|
A
-
E
-
N
-
L
-
Y
-
F
-
Q
-
L
-
E
-
E
-
40
|
L
-
E
-
L
M
D
T
E
L
Q
Q
Q
Q
R
R
K
K
R
R
50
|
L
L
E
E
A
A
F
F
L
L
T
T
Q
Q
K
K
Q
Q
K
K
60
|
V
V
G
G
E
E
L
L
K
K
D
D
D
D
D
D
F
F
E
E
70
|
K
K
I
I
S
S
E
E
L
L
G
G
A
A
G
G
N
N
G
G
80
|
G
G
V
V
V
V
F
F
K
K
V
V
S
S
H
H
K
K
P
P
90
|
S
S
G
G
L
L
V
V
M
M
A
A
R
R
K
K
L
L
I
I
100
|
H
H
L
L
E
E
I
I
K
K
P
P
A
A
I
I
R
R
N
N
110
|
Q
Q
I
I
I
I
R
R
E
E
L
L
Q
Q
V
V
L
L
H
H
120
|
E
E
C
S
N
N
S
S
P
P
Y
Y
I
I
V
V
G
G
F
F
130
|
Y
Y
G
G
A
A
F
F
Y
Y
S
S
D
D
G
G
E
E
I
I
140
|
S
S
I
I
C
C
M
M
E
E
H
H
M
M
D
D
G
G
G
G
150
|
S
S
L
L
D
D
Q
Q
V
V
L
L
K
K
K
K
A
A
G
G
160
|
R
R
I
I
P
P
E
E
Q
Q
I
I
L
L
G
G
K
K
V
V
170
|
S
S
I
I
A
A
V
V
I
I
K
K
G
G
L
L
T
T
Y
Y
180
|
L
L
R
R
E
E
K
K
H
H
K
K
I
I
M
M
H
H
R
R
190
|
D
D
V
V
K
K
P
P
S
S
N
N
I
I
L
L
V
V
N
N
200
|
S
S
R
R
G
G
E
E
I
I
K
K
L
L
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 PLX4720 by unusual activation of pro-survival pathway
Key Molecule: MAPK/ERK kinase 1 (MEK1) [8]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
 Disease Info 
Molecule Alteration Missense mutation
p.F53L (c.157T>C)
 Molecule Info 
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.F53L (c.157T>C) in gene MAP2K1 cause the sensitivity of PLX4720 by unusual activation of pro-survival pathway
Key Molecule: MAPK/ERK kinase 1 (MEK1) [8]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
 Disease Info 
Molecule Alteration Missense mutation
p.Q56P (c.167A>C)
 Molecule Info 
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.Q56P (c.167A>C) in gene MAP2K1 cause the sensitivity of PLX4720 by unusual activation of pro-survival pathway
Key Molecule: MAPK/ERK kinase 1 (MEK1) [8]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
 Disease Info 
Molecule Alteration Missense mutation
p.K57N (c.171G>C)
 Molecule Info 
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.K57N (c.171G>C) in gene MAP2K1 cause the sensitivity of PLX4720 by unusual activation of pro-survival pathway
Key Molecule: MAPK/ERK kinase 1 (MEK1) [8]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
 Disease Info 
Molecule Alteration Missense mutation
p.I111S (c.332T>G)
 Molecule Info 
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.I111S (c.332T>G) in gene MAP2K1 cause the sensitivity of PLX4720 by unusual activation of pro-survival pathway
Key Molecule: MAPK/ERK kinase 1 (MEK1) [8]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
 Disease Info 
Molecule Alteration Missense mutation
p.F129L (c.385T>C)
 Molecule Info 
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.F129L (c.385T>C) in gene MAP2K1 cause the sensitivity of PLX4720 by unusual activation of pro-survival pathway
Key Molecule: MAPK/ERK kinase 1 (MEK1) [8]
Sensitive Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z]
 Disease Info 
Molecule Alteration Missense mutation
p.V211D (c.632T>A)
 Molecule Info 
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.V211D (c.632T>A) in gene MAP2K1 cause the sensitivity of PLX4720 by unusual activation of pro-survival pathway
Colon cancer [ICD-11: 2B90]
Click to Show/Hide
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [5]
Sensitive Disease Colon cancer [ICD-11: 2B90.1]
 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
-
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
Experiment for
Drug Resistance		 CellTiter-Glo luminescent cell viability assay
Mechanism Description The missense mutation p.V600E (c.1799T>A) in gene BRAF cause the sensitivity of PLX4720 by aberration of the drug's therapeutic target
Melanoma [ICD-11: 2C30]
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: Guanine nucleotide-binding protein alpha-q (GNAQ) [3]
Resistant Disease Melanoma [ICD-11: 2C30.0]
 Disease Info 
Molecule Alteration Missense mutation
p.Q209P (c.626A>C)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
In Vitro Model A375 cells Skin Homo sapiens (Human) CVCL_0132
Experiment for
Molecule Alteration		 Sanger sequencing assay; SNP array; qPCR
Experiment for
Drug Resistance		 CellTiter-Glo assay
Key Molecule: MAPK/ERK kinase 1 (MEK1) [4]
Resistant Disease Melanoma [ICD-11: 2C30.0]
 Disease Info 
Molecule Alteration Missense mutation
p.Q56P (c.167A>C)
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
In Vitro Model A375 cells Skin Homo sapiens (Human) CVCL_0132
293T cells Breast Homo sapiens (Human) CVCL_0063
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 Colony formation assay
Mechanism Description The missense mutation p.Q56P (c.167A>C) in gene MAP2K1 cause the resistance of PLX4720 by unusual activation of pro-survival pathway
Key Molecule: GTPase Nras (NRAS) [1]
Resistant Disease Melanoma [ICD-11: 2C30.0]
 Disease Info 
Molecule Alteration Missense mutation
p.Q61L (c.182A>T)
 Molecule Info 
Experimental Note Identified from the Human Clinical Data
Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
  Aberration of the Drug's Therapeutic Target (ADTT) Click to Show/Hide
Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [5]
Sensitive Disease 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
|
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
Experiment for
Drug Resistance		 CellTiter-Glo luminescent cell viability assay
Mechanism Description The missense mutation p.V600E (c.1799T>A) in gene BRAF cause the sensitivity of PLX4720 by aberration of the drug's therapeutic target
References
Ref 1 Paradox-breaking RAF inhibitors that also target SRC are effective in drug-resistant BRAF mutant melanomaCancer Cell. 2015 Jan 12;27(1):85-96. doi: 10.1016/j.ccell.2014.11.006. Epub 2014 Dec 11.
Ref 2 Targeting a Plk1-Controlled Polarity Checkpoint in Therapy-Resistant Glioblastoma-Propagating CellsCancer Res. 2015 Dec 15;75(24):5355-66. doi: 10.1158/0008-5472.CAN-14-3689. Epub 2015 Nov 16.
Ref 3 Whole-genome sequencing reveals complex mechanisms of intrinsic resistance to BRAF inhibitionAnn Oncol. 2014 May;25(5):959-67. doi: 10.1093/annonc/mdu049. Epub 2014 Feb 6.
Ref 4 MEK1 mutations confer resistance to MEK and B-RAF inhibitionProc Natl Acad Sci U S A. 2009 Dec 1;106(48):20411-6. doi: 10.1073/pnas.0905833106. Epub 2009 Nov 13.
Ref 5 Discovery of a selective inhibitor of oncogenic B-Raf kinase with potent antimelanoma activityProc Natl Acad Sci U S A. 2008 Feb 26;105(8):3041-6. doi: 10.1073/pnas.0711741105. Epub 2008 Feb 19.
Ref 6 Targeted therapy for BRAFV600E malignant astrocytomaClin Cancer Res. 2011 Dec 15;17(24):7595-604. doi: 10.1158/1078-0432.CCR-11-1456. Epub 2011 Oct 28.
Ref 7 Gatekeeper mutations mediate resistance to BRAF-targeted therapiesSci Transl Med. 2010 Jun 9;2(35):35ra41. doi: 10.1126/scitranslmed.3000758.
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.

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