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
• 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]
• 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]
• Target: Fms-like tyrosine kinase 3 (FLT-3); FLT3_HUMAN; [1]
• Target: Platelet-derived growth factor receptor (PDGFR); NOUNIPROTAC; [1]
• Target: Vascular endothelial growth factor receptor (VEGFR); NOUNIPROTAC; [1]
• 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

Lung cancer [ICD-11: 2C25]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-200b [1]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: PC3 cells; Prostate; Homo sapiens (Human); CVCL_0035
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: NCI-H1650 cells; Lung; Homo sapiens (Human); CVCL_1483
• In Vitro Model: PC9 cells; Lung; Homo sapiens (Human); CVCL_B260
• In Vitro Model: NCI-H1975 cells; Lung; Homo sapiens (Human); CVCL_1511
• In Vitro Model: PC-14 cells; Lung; Homo sapiens (Human); CVCL_1640
• In Vitro Model: EBC-1 cells; Lung; Homo sapiens (Human); CVCL_2891
• In Vitro Model: LC-1/sq cells; Lung; Homo sapiens (Human); CVCL_3008
• In Vitro Model: LC-2/ad cells; Lung; Homo sapiens (Human); CVCL_1373
• In Vitro Model: Lk-2 cells; Lung; Homo sapiens (Human); CVCL_1377
• In Vitro Model: NCI-HCC827 cells; Lung; Homo sapiens (Human); CVCL_2063
• In Vitro Model: PC-1 cells; Pancreas; Homo sapiens (Human); CVCL_S978
• In Vitro Model: PC-10 cells; Lung; Homo sapiens (Human); CVCL_7088
• In Vitro Model: QG56 cells; Lung; Homo sapiens (Human); CVCL_6943
• In Vitro Model: RERF-LCkJ cells; Lung; Homo sapiens (Human); CVCL_1654
• In Vitro Model: 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]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: PC3 cells; Prostate; Homo sapiens (Human); CVCL_0035
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: NCI-H1650 cells; Lung; Homo sapiens (Human); CVCL_1483
• In Vitro Model: PC9 cells; Lung; Homo sapiens (Human); CVCL_B260
• In Vitro Model: NCI-H1975 cells; Lung; Homo sapiens (Human); CVCL_1511
• In Vitro Model: PC-14 cells; Lung; Homo sapiens (Human); CVCL_1640
• In Vitro Model: EBC-1 cells; Lung; Homo sapiens (Human); CVCL_2891
• In Vitro Model: LC-1/sq cells; Lung; Homo sapiens (Human); CVCL_3008
• In Vitro Model: LC-2/ad cells; Lung; Homo sapiens (Human); CVCL_1373
• In Vitro Model: Lk-2 cells; Lung; Homo sapiens (Human); CVCL_1377
• In Vitro Model: NCI-HCC827 cells; Lung; Homo sapiens (Human); CVCL_2063
• In Vitro Model: PC-1 cells; Pancreas; Homo sapiens (Human); CVCL_S978
• In Vitro Model: PC-10 cells; Lung; Homo sapiens (Human); CVCL_7088
• In Vitro Model: QG56 cells; Lung; Homo sapiens (Human); CVCL_6943
• In Vitro Model: RERF-LCkJ cells; Lung; Homo sapiens (Human); CVCL_1654
• In Vitro Model: 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]

• Molecule Alteration: Expression; Up-regulation
• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: PC3 cells; Prostate; Homo sapiens (Human); CVCL_0035
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: NCI-H1650 cells; Lung; Homo sapiens (Human); CVCL_1483
• In Vitro Model: PC9 cells; Lung; Homo sapiens (Human); CVCL_B260
• In Vitro Model: NCI-H1975 cells; Lung; Homo sapiens (Human); CVCL_1511
• In Vitro Model: PC-14 cells; Lung; Homo sapiens (Human); CVCL_1640
• In Vitro Model: EBC-1 cells; Lung; Homo sapiens (Human); CVCL_2891
• In Vitro Model: LC-1/sq cells; Lung; Homo sapiens (Human); CVCL_3008
• In Vitro Model: LC-2/ad cells; Lung; Homo sapiens (Human); CVCL_1373
• In Vitro Model: Lk-2 cells; Lung; Homo sapiens (Human); CVCL_1377
• In Vitro Model: NCI-HCC827 cells; Lung; Homo sapiens (Human); CVCL_2063
• In Vitro Model: PC-1 cells; Pancreas; Homo sapiens (Human); CVCL_S978
• In Vitro Model: PC-10 cells; Lung; Homo sapiens (Human); CVCL_7088
• In Vitro Model: QG56 cells; Lung; Homo sapiens (Human); CVCL_6943
• In Vitro Model: RERF-LCkJ cells; Lung; Homo sapiens (Human); CVCL_1654
• In Vitro Model: 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.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Zinc finger E-box-binding homeobox 1 (ZEB1) [1]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: PC3 cells; Prostate; Homo sapiens (Human); CVCL_0035
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: NCI-H1650 cells; Lung; Homo sapiens (Human); CVCL_1483
• In Vitro Model: PC9 cells; Lung; Homo sapiens (Human); CVCL_B260
• In Vitro Model: NCI-H1975 cells; Lung; Homo sapiens (Human); CVCL_1511
• In Vitro Model: PC-14 cells; Lung; Homo sapiens (Human); CVCL_1640
• In Vitro Model: EBC-1 cells; Lung; Homo sapiens (Human); CVCL_2891
• In Vitro Model: LC-1/sq cells; Lung; Homo sapiens (Human); CVCL_3008
• In Vitro Model: LC-2/ad cells; Lung; Homo sapiens (Human); CVCL_1373
• In Vitro Model: Lk-2 cells; Lung; Homo sapiens (Human); CVCL_1377
• In Vitro Model: NCI-HCC827 cells; Lung; Homo sapiens (Human); CVCL_2063
• In Vitro Model: PC-1 cells; Pancreas; Homo sapiens (Human); CVCL_S978
• In Vitro Model: PC-10 cells; Lung; Homo sapiens (Human); CVCL_7088
• In Vitro Model: QG56 cells; Lung; Homo sapiens (Human); CVCL_6943
• In Vitro Model: RERF-LCkJ cells; Lung; Homo sapiens (Human); CVCL_1654
• In Vitro Model: 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.

Multiple endocrine neoplasia [ICD-11: 2F7A]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Proto-oncogene tyrosine-protein kinase receptor Ret (RET) [2]

• Molecule Alteration: Missense mutation; p.M918T
• Resistant Disease: Multiple endocrine neoplasia [ICD-11: 2F7A.0]
• 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]

• Molecule Alteration: Missense mutation; p.M918T
• Resistant Disease: Multiple endocrine neoplasia [ICD-11: 2F7A.0]
• 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