Drug Information

Drug (ID: DG00128) and It's Reported Resistant Information
Name
Intedanib
Synonyms
Nintedanib; Vargatef; 656247-17-5; BIBF-1120; BIBF 1120; 928326-83-4; BIBF1120; Nintedanib (BIBF 1120); OFEV; UNII-G6HRD2P839; (Z)-methyl 3-((4-(N-methyl-2-(4-methylpiperazin-1-yl)acetamido)phenylamino)(phenyl)methylene)-2-oxoindoline-6-carboxylate; G6HRD2P839; CHEBI:85164; 1160294-26-7; Methyl (3z)-3-{[(4-{methyl[(4-Methylpiperazin-1-Yl)acetyl]amino}phenyl)amino](Phenyl)methylidene}-2-Oxo-2,3-Dihydro-1h-Indole-6-Carboxylate
    Click to Show/Hide
Indication
In total 5 Indication(s)
Colorectal cancer [ICD-11: 2B91]
Approved
[1]
Idiopathic interstitial pneumonitis [ICD-11: CB03]
Approved
[1]
Lung cancer [ICD-11: 2C25]
Phase 3
[1]
Peritoneal cancer [ICD-11: 2C51]
Phase 3
[1]
Ovarian cancer [ICD-11: 2C73]
Phase 2
[1]
Structure
Drug Resistance Disease(s)
Disease(s) with Clinically Reported Resistance for This Drug (1 diseases)
Multiple endocrine neoplasia [ICD-11: 2F7A]
[2]
Target Fibroblast growth factor receptor 1 (FGFR1) FGFR1_HUMAN [1]
Fms-like tyrosine kinase 3 (FLT-3) FLT3_HUMAN [1]
Platelet-derived growth factor receptor (PDGFR) NOUNIPROTAC [1]
Vascular endothelial growth factor receptor (VEGFR) NOUNIPROTAC [1]
Click to Show/Hide the Molecular Information and External Link(s) of This Drug
Formula
C31H33N5O4
IsoSMILES
CN1CCN(CC1)CC(=O)N(C)C2=CC=C(C=C2)N=C(C3=CC=CC=C3)C4=C(NC5=C4C=CC(=C5)C(=O)OC)O
InChI
1S/C31H33N5O4/c1-34-15-17-36(18-16-34)20-27(37)35(2)24-12-10-23(11-13-24)32-29(21-7-5-4-6-8-21)28-25-14-9-22(31(39)40-3)19-26(25)33-30(28)38/h4-14,19,33,38H,15-18,20H2,1-3H3
InChIKey
CPMDPSXJELVGJG-UHFFFAOYSA-N
PubChem CID
135423438
ChEBI ID
CHEBI:85164
TTD Drug ID
D09HNV
VARIDT ID
DR00137
DrugBank ID
DB09079
Type(s) of Resistant Mechanism of This Drug
  EADR: Epigenetic Alteration of DNA, RNA or Protein
  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
Lung cancer [ICD-11: 2C25]
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: Zinc finger E-box-binding homeobox 1 (ZEB1) [1]
Sensitive Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Molecule Alteration Expression
Down-regulation
 Molecule Info 
Differential expression of the molecule in resistant disease
Classification of Disease Lung cancer [ICD-11: 2C25]
The Specified Disease Non-small cell lung cancer
The Studied Tissue Lung tissue
The Expression Level of Disease Section Compare with the Healthy Individual Tissue
p-value: 1.74E-02
Fold-change: -1.61E-01
Z-score: -2.40E+00
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
Cell proliferation Inhibition hsa05200
In Vitro Model PC3 cells Prostate Homo sapiens (Human) CVCL_0035
A549 cells Lung Homo sapiens (Human) CVCL_0023
NCI-H1650 cells Lung Homo sapiens (Human) CVCL_1483
PC9 cells Lung Homo sapiens (Human) CVCL_B260
NCI-H1975 cells Lung Homo sapiens (Human) CVCL_1511
PC-14 cells Lung Homo sapiens (Human) CVCL_1640
EBC-1 cells Lung Homo sapiens (Human) CVCL_2891
LC-1/sq cells Lung Homo sapiens (Human) CVCL_3008
LC-2/ad cells Lung Homo sapiens (Human) CVCL_1373
Lk-2 cells Lung Homo sapiens (Human) CVCL_1377
NCI-HCC827 cells Lung Homo sapiens (Human) CVCL_2063
PC-1 cells Pancreas Homo sapiens (Human) CVCL_S978
PC-10 cells Lung Homo sapiens (Human) CVCL_7088
QG56 cells Lung Homo sapiens (Human) CVCL_6943
RERF-LCkJ cells Lung Homo sapiens (Human) CVCL_1654
SQ5 cells Lung Homo sapiens (Human) CVCL_8273
Experiment for
Molecule Alteration		 Western blot analysis
Experiment for
Drug Resistance		 MTS assay
Mechanism Description miR-200b and miR-141 associated with epithelial-mesenchymal transition (EMT) are predictive biomarkers and therapeutic targets of nintedanib in NSCLC cells. nintedanib inhibited EMT and reversed the resistance to EGFR-TkI with TGF-beta-induced EMT through miR-200 family induction in NSCLC cells. low expression of miR-200b and miR-141, resulting in high level of ZEB1 and low level of E-cadherin, was associated with the resistance to nintedanib in NSCLC cells.
  Epigenetic Alteration of DNA, RNA or Protein (EADR) Click to Show/Hide
Key Molecule: hsa-mir-200b [1]
Sensitive Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
Cell proliferation Inhibition hsa05200
In Vitro Model PC3 cells Prostate Homo sapiens (Human) CVCL_0035
A549 cells Lung Homo sapiens (Human) CVCL_0023
NCI-H1650 cells Lung Homo sapiens (Human) CVCL_1483
PC9 cells Lung Homo sapiens (Human) CVCL_B260
NCI-H1975 cells Lung Homo sapiens (Human) CVCL_1511
PC-14 cells Lung Homo sapiens (Human) CVCL_1640
EBC-1 cells Lung Homo sapiens (Human) CVCL_2891
LC-1/sq cells Lung Homo sapiens (Human) CVCL_3008
LC-2/ad cells Lung Homo sapiens (Human) CVCL_1373
Lk-2 cells Lung Homo sapiens (Human) CVCL_1377
NCI-HCC827 cells Lung Homo sapiens (Human) CVCL_2063
PC-1 cells Pancreas Homo sapiens (Human) CVCL_S978
PC-10 cells Lung Homo sapiens (Human) CVCL_7088
QG56 cells Lung Homo sapiens (Human) CVCL_6943
RERF-LCkJ cells Lung Homo sapiens (Human) CVCL_1654
SQ5 cells Lung Homo sapiens (Human) CVCL_8273
In Vivo Model Nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 MTS assay
Mechanism Description miR-200b and miR-141 associated with epithelial-mesenchymal transition (EMT) are predictive biomarkers and therapeutic targets of nintedanib in NSCLC cells. nintedanib inhibited EMT and reversed the resistance to EGFR-TkI with TGF-beta-induced EMT through miR-200 family induction in NSCLC cells. low expression of miR-200b and miR-141, resulting in high level of ZEB1 and low level of E-cadherin, was associated with the resistance to nintedanib in NSCLC cells.
Key Molecule: hsa-mir-200c [1]
Sensitive Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
Cell proliferation Inhibition hsa05200
In Vitro Model PC3 cells Prostate Homo sapiens (Human) CVCL_0035
A549 cells Lung Homo sapiens (Human) CVCL_0023
NCI-H1650 cells Lung Homo sapiens (Human) CVCL_1483
PC9 cells Lung Homo sapiens (Human) CVCL_B260
NCI-H1975 cells Lung Homo sapiens (Human) CVCL_1511
PC-14 cells Lung Homo sapiens (Human) CVCL_1640
EBC-1 cells Lung Homo sapiens (Human) CVCL_2891
LC-1/sq cells Lung Homo sapiens (Human) CVCL_3008
LC-2/ad cells Lung Homo sapiens (Human) CVCL_1373
Lk-2 cells Lung Homo sapiens (Human) CVCL_1377
NCI-HCC827 cells Lung Homo sapiens (Human) CVCL_2063
PC-1 cells Pancreas Homo sapiens (Human) CVCL_S978
PC-10 cells Lung Homo sapiens (Human) CVCL_7088
QG56 cells Lung Homo sapiens (Human) CVCL_6943
RERF-LCkJ cells Lung Homo sapiens (Human) CVCL_1654
SQ5 cells Lung Homo sapiens (Human) CVCL_8273
In Vivo Model Nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 MTS assay
Mechanism Description miR-200b and miR-141 associated with epithelial-mesenchymal transition (EMT) are predictive biomarkers and therapeutic targets of nintedanib in NSCLC cells. nintedanib inhibited EMT and reversed the resistance to EGFR-TkI with TGF-beta-induced EMT through miR-200 family induction in NSCLC cells. low expression of miR-200b and miR-141, resulting in high level of ZEB1 and low level of E-cadherin, was associated with the resistance to nintedanib in NSCLC cells.
Key Molecule: hsa-mir-141 [1]
Sensitive Disease Non-small cell lung cancer [ICD-11: 2C25.Y]
 Disease Info 
Molecule Alteration Expression
Up-regulation
 Molecule Info 
Experimental Note Revealed Based on the Cell Line Data
Cell Pathway Regulation Cell apoptosis Activation hsa04210
Cell proliferation Inhibition hsa05200
In Vitro Model PC3 cells Prostate Homo sapiens (Human) CVCL_0035
A549 cells Lung Homo sapiens (Human) CVCL_0023
NCI-H1650 cells Lung Homo sapiens (Human) CVCL_1483
PC9 cells Lung Homo sapiens (Human) CVCL_B260
NCI-H1975 cells Lung Homo sapiens (Human) CVCL_1511
PC-14 cells Lung Homo sapiens (Human) CVCL_1640
EBC-1 cells Lung Homo sapiens (Human) CVCL_2891
LC-1/sq cells Lung Homo sapiens (Human) CVCL_3008
LC-2/ad cells Lung Homo sapiens (Human) CVCL_1373
Lk-2 cells Lung Homo sapiens (Human) CVCL_1377
NCI-HCC827 cells Lung Homo sapiens (Human) CVCL_2063
PC-1 cells Pancreas Homo sapiens (Human) CVCL_S978
PC-10 cells Lung Homo sapiens (Human) CVCL_7088
QG56 cells Lung Homo sapiens (Human) CVCL_6943
RERF-LCkJ cells Lung Homo sapiens (Human) CVCL_1654
SQ5 cells Lung Homo sapiens (Human) CVCL_8273
In Vivo Model Nude mouse xenograft model Mus musculus
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 MTS assay
Mechanism Description miR-200b and miR-141 associated with epithelial-mesenchymal transition (EMT) are predictive biomarkers and therapeutic targets of nintedanib in NSCLC cells. nintedanib inhibited EMT and reversed the resistance to EGFR-TkI with TGF-beta-induced EMT through miR-200 family induction in NSCLC cells. low expression of miR-200b and miR-141, resulting in high level of ZEB1 and low level of E-cadherin, was associated with the resistance to nintedanib in NSCLC cells.
Multiple endocrine neoplasia [ICD-11: 2F7A]
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: Proto-oncogene tyrosine-protein kinase receptor Ret (RET) [2]
Resistant Disease Multiple endocrine neoplasia [ICD-11: 2F7A.0]
 Disease Info 
Molecule Alteration Missense mutation
p.M918T
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.64  Å
PDB: 7DUA
Mutant Type Structure Method: X-ray diffraction Resolution: 2.12  Å
PDB: 4CKI
   Download The Information of Sequence       Download The Structure File   
RMSD: 0.93
TM score: 0.95555
Amino acid change:
M918T
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
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700
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G
G
P
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L
L
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D
D
A
A
F
F
710
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I
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E
E
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D
P
P
K
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W
W
E
E
F
F
720
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P
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R
R
K
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N
N
L
L
V
V
L
L
G
G
K
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T
T
730
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L
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G
G
E
E
G
G
E
E
F
F
G
G
K
K
V
V
V
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740
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K
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A
A
T
T
A
A
F
F
H
H
L
L
K
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G
G
R
R
750
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A
A
G
G
Y
Y
T
T
T
T
V
V
A
A
V
V
K
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M
M
760
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L
L
K
K
E
E
N
N
A
A
S
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P
P
S
S
E
E
L
L
770
|
R
R
D
D
L
L
L
L
S
S
E
E
F
F
N
N
V
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L
L
780
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K
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Q
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V
V
N
N
H
H
P
P
H
H
V
V
I
I
K
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790
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L
L
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Y
G
G
A
A
C
C
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G
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800
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L
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I
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E
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Y
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810
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R
G
G
F
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820
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V
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G
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P
P
G
G
Y
Y
L
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830
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G
G
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G
S
S
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R
N
N
S
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L
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D
D
840
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H
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P
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D
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E
E
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850
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860
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Y
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E
E
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M
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870
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L
L
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H
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L
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A
A
A
A
R
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N
N
880
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E
E
G
G
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R
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890
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I
I
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S
D
D
F
F
G
G
L
L
S
S
R
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900
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Y
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E
E
E
E
D
D
S
S
Y
Y
V
V
K
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S
S
910
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Q
Q
G
G
R
R
I
I
P
P
V
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A
A
920
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I
I
E
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S
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L
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D
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T
930
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940
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L
L
L
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W
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E
E
I
I
V
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T
T
L
L
G
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G
G
950
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N
N
P
P
Y
Y
P
P
G
G
I
I
P
P
P
P
E
E
R
R
960
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L
L
F
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N
N
L
L
L
L
K
K
T
T
G
G
H
H
R
R
970
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M
M
E
E
R
R
P
P
D
D
N
N
C
C
S
S
E
E
E
E
980
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M
M
Y
Y
R
R
L
L
M
M
L
L
Q
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C
C
W
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990
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Q
Q
E
E
P
P
D
D
K
K
R
R
P
P
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A
A
1000
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D
D
I
I
S
S
K
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D
D
L
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E
K
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M
M
M
M
1010
|
V
V
K
K
R
R
R
R
Click to Show/Hide the Structure
Experimental Note Identified from the Human Clinical Data
In Vitro Model BaF3 cells Bone Mus musculus (Mouse) CVCL_0161
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 LC50 assay
Mechanism Description M918T is a RET mutation prevalent in aggressive multiple endocrine neoplasia type 2B. M918T mutation is located at distant sites away from the TKI binding pocket. IC50s of cabozantinib, lenvatinib, vandetanib and nintedanib in BaF3/KR (M918T) cells were 6.5-fold, 7.5-fold, 4.3-fold and 1.7-fold, respectively, higher than in BaF3/KR cells.
Key Molecule: Proto-oncogene tyrosine-protein kinase receptor Ret (RET) [2]
Resistant Disease Multiple endocrine neoplasia [ICD-11: 2F7A.0]
 Disease Info 
Molecule Alteration Missense mutation
p.M918T
 Molecule Info 
Wild Type Structure Method: X-ray diffraction Resolution: 1.64  Å
PDB: 7DUA
Mutant Type Structure Method: X-ray diffraction Resolution: 2.12  Å
PDB: 4CKI
   Download The Information of Sequence       Download The Structure File   
RMSD: 0.93
TM score: 0.95555
Amino acid change:
M918T
 : Wild Type Structure
 : Mutant Type Structure
  Mutation site(s) have been marked in red
-
700
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G
G
P
P
L
L
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S
L
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S
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V
V
D
D
A
A
F
F
710
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720
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730
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740
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A
A
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A
A
F
F
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750
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A
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760
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L
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E
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770
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780
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790
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L
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800
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L
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Y
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A
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Y
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810
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G
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L
L
R
R
G
G
F
F
L
L
R
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E
E
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820
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R
R
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K
V
V
G
G
P
P
G
G
Y
Y
L
L
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S
830
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G
G
G
G
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S
R
R
N
N
S
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840
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H
H
P
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850
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D
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L
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F
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860
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Q
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G
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M
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870
|
L
L
V
V
H
H
R
R
D
D
L
L
A
A
A
A
R
R
N
N
880
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I
I
L
L
V
V
A
A
E
E
G
G
R
R
K
K
M
M
K
K
890
|
I
I
S
S
D
D
F
F
G
G
L
L
S
S
R
R
D
D
V
V
900
|
Y
Y
E
E
E
E
D
D
S
S
Y
Y
V
V
K
K
R
R
S
S
910
|
Q
Q
G
G
R
R
I
I
P
P
V
V
K
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W
W
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920
|
I
I
E
E
S
S
L
L
F
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D
H
H
I
I
Y
Y
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T
930
|
T
T
Q
Q
S
S
D
D
V
V
W
W
S
S
F
F
G
G
V
V
940
|
L
L
L
L
W
W
E
E
I
I
V
V
T
T
L
L
G
G
G
G
950
|
N
N
P
P
Y
Y
P
P
G
G
I
I
P
P
P
P
E
E
R
R
960
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L
L
F
F
N
N
L
L
L
L
K
K
T
T
G
G
H
H
R
R
970
|
M
M
E
E
R
R
P
P
D
D
N
N
C
C
S
S
E
E
E
E
980
|
M
M
Y
Y
R
R
L
L
M
M
L
L
Q
Q
C
C
W
W
K
K
990
|
Q
Q
E
E
P
P
D
D
K
K
R
R
P
P
V
V
F
F
A
A
1000
|
D
D
I
I
S
S
K
K
D
D
L
L
E
E
K
K
M
M
M
M
1010
|
V
V
K
K
R
R
R
R
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Experimental Note Identified from the Human Clinical Data
In Vitro Model BaF3 cells Bone Mus musculus (Mouse) CVCL_0161
Experiment for
Molecule Alteration		 qRT-PCR
Experiment for
Drug Resistance		 LC50 assay
Mechanism Description M918T is a RET mutation prevalent in aggressive multiple endocrine neoplasia type 2B. M918T mutation is located at distant sites away from the TKI binding pocket. IC50s of cabozantinib, lenvatinib, vandetanib and nintedanib in BaF3/KR (M918T) cells were 6.5-fold, 7.5-fold, 4.3-fold and 1.7-fold, respectively, higher than in BaF3/KR cells.
References
Ref 1 miR-200/ZEB axis regulates sensitivity to nintedanib in non-small cell lung cancer cells. Int J Oncol. 2016 Mar;48(3):937-44. doi: 10.3892/ijo.2016.3331. Epub 2016 Jan 11.
Ref 2 Drug resistance profiles of mutations in the RET kinase domain .Br J Pharmacol. 2018 Sep;175(17):3504-3515. doi: 10.1111/bph.14395. Epub 2018 Jul 19. 10.1111/bph.14395

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