Drug Information

Drug (ID: DG00619) and It's Reported Resistant Information

• Name: Vandetanib
• Synonyms: Vandetanib; 443913-73-3; Zactima; ZD6474; Caprelsa; N-(4-Bromo-2-fluorophenyl)-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazolin-4-amine; vandetanib (zd6474); ZD 6474; ZD-6474; N-(4-bromo-2-fluorophenyl)-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinazolin-4-amine; UNII-YO460OQ37K; C22H24BrFN4O2; CHEMBL24828; N-(4-Bromo-2-fluorophenyl)-6-methoxy-7-((1-methyl-4-piperidinyl)methoxy)-4-quinazolinamine; YO460OQ37K; CHEBI:49960; GNF-PF-2188; MFCD07772346; NSC-744325; NSC-760766; NCGC00167513-01; 4-[(4-Bromo-2-fluorophenyl)amino]-6-methoxy-7-[(1-methyl-4-piperidyl)methoxy]quinazoline; DSSTox_CID_26681; DSSTox_RID_81816; DSSTox_GSID_46681; 4-(4-Bromo-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-yl)methoxyquinazoline; N-(4-Bromo-2-fluorophenyl)-6-methoxy-7-[(1-methyl-4-piperidinyl)methoxy]-4-quinazolinamine; (4-Bromo-2-fluoro-phenyl)-[6-methoxy-7-(1-methyl-piperidin-4-ylmethoxy)-quinazolin-4-yl]-amine; CAS-443913-73-3; Vandetinib; HSDB 8198; 2ivu; Vandetanib [USAN:INN:BAN:JAN]; ZD-64; Caprelsa (TN); AZD-6474; Vandetanib- Bio-X; CH 331; CH-331; Vandetanib (Zactima); DMPC Cyclic Urea 1; Kinome_3316; BDBM21; SCHEMBL9044; MLS006011672; Vandetanib (JAN/USAN/INN); AMY599; F9995-0087; GTPL5717; QCR-37; DTXSID1046681; SCHEMBL21067679; cid_3081361; EX-A422; SYN1090; BCPP000023; HMS3244K03; HMS3244K04; HMS3244L03; HMS3654E11; HMS3672C07; AOB87780; BCP01925; Tox21_112511; 443913-73-3 (free base); NSC744325; NSC760766; NSC800961; s1046; ZINC53683345; AKOS015902350; Tox21_112511_1; AC-5251; CCG-269495; CS-0130; DB05294; MCULE-4705827953; NSC 744325; NSC 760766; NSC-800961; SB16919; 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline; NCGC00167513-02; NCGC00167513-03; NCGC00167513-04; NCGC00167513-09; 338992-00-0; 4-BROMO-2-FLUORO-N-[(4E)-6-METHOXY-7-[(1-METHYLPIPERIDIN-4-YL)METHOXY]QUINAZOLIN-4(1H)-YLIDENE]ANILINE; 4-Quninazolinamine, N-(4-bromo-2-fluorophenyl)-6-methoxy-7-((1-methyl-4-piperidinyl)methoxy)-; AS-11067; BV164508; HY-10260; SMR002530472; SY027438; FT-0656736; SW218092-2; EC-000.2359; A25648; D06407; V-9402; AB01273969-01; AB01273969-02; AB01273969_04; 913V733; SR-00000000462; Q7914515; SR-00000000462-2; BRD-K77625799-001-01-0; 4-(4-Bromo-2-fluoroanilino)-6-methoxy- 7-[(1-methylpiperidin-4-yl)methoxy]quinazoline; 6-[(4R,5S,6S,7R)-4,7-dibenzyl-3-(5-carboxypentyl)-5,6-dihydroxy-2-oxo-1,3-diazepan-1-yl]hexanoic acid; Quinazolin-4-amine, N-(4-bromo-2-fluorophenyl)-6-mthoxy-7-[(1-methyl-4-piperidinyl)methoxy]-; Vandetanib;7-((4-aminocyclohexyl)methoxy)-N-(4-bromo-2-fluorophenyl)-6-methoxyquinazolin-4-amine; ZD6
• Indication:
  In total 1 Indication(s)
  Solid tumour/cancer [ICD-11: 2A00-2F9Z]; Approved; [1]
• Drug Resistance Disease(s):
  Disease(s) with Clinically Reported Resistance for This Drug (1 diseases)
  Multiple endocrine neoplasia [ICD-11: 2F7A]; [1]
  Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (1 diseases)
  Solid tumour/cancer [ICD-11: 2A00-2F9Z]; [2]
• Target: Epidermal growth factor receptor (EGFR); EGFR_HUMAN; [1]
• Target: Proto-oncogene c-Ret (RET); RET_HUMAN; [1]
• Target: Vascular endothelial growth factor receptor 2 (KDR); VGFR2_HUMAN; [1]
• Formula: C22H24BrFN4O2
• IsoSMILES: CN1CCC(CC1)COC2=C(C=C3C(=C2)N=CN=C3NC4=C(C=C(C=C4)Br)F)OC
• InChI: 1S/C22H24BrFN4O2/c1-28-7-5-14(6-8-28)12-30-21-11-19-16(10-20(21)29-2)22(26-13-25-19)27-18-4-3-15(23)9-17(18)24/h3-4,9-11,13-14H,5-8,12H2,1-2H3,(H,25,26,27)
• InChIKey: UHTHHESEBZOYNR-UHFFFAOYSA-N
• PubChem CID: 3081361
• ChEBI ID: CHEBI:49960
• TTD Drug ID: D0G6QF
• VARIDT ID: DR00618
• INTEDE ID: DR1669
• DrugBank ID: DB05294

Type(s) of Resistant Mechanism of This Drug

  ADTT: Aberration of the Drug's Therapeutic Target

  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

Solid tumour/cancer [ICD-11: 2A00-2F9Z]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

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

• Molecule Alteration: Missense mutation; p.V804M (c.2410G>A)
• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HEK293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• Experiment for Molecule Alteration: Immunoblotting assay
• Experiment for Drug Resistance: Growth curves and transformation assay
• Mechanism Description: The missense mutation p.V804M (c.2410G>A) in gene RET cause the resistance of Vandetanib by aberration of the drug's therapeutic target

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

• Molecule Alteration: Missense mutation; p.V804L (c.2410G>C)
• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HEK293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• Experiment for Molecule Alteration: Immunoblotting assay
• Experiment for Drug Resistance: Growth curves and transformation assay
• Mechanism Description: The missense mutation p.V804L (c.2410G>C) in gene RET cause the resistance of Vandetanib by aberration of the drug's therapeutic target

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

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

• Molecule Alteration: Missense mutation; p.C634R (c.1900T>C)
• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HEK293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• Experiment for Molecule Alteration: Immunoblotting assay
• Experiment for Drug Resistance: Growth curves and transformation assay
• Mechanism Description: The missense mutation p.C634R (c.1900T>C) in gene RET cause the sensitivity of Vandetanib by aberration of the drug's therapeutic target

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

• Molecule Alteration: Missense mutation; p.E768D (c.2304G>C)
• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HEK293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• Experiment for Molecule Alteration: Immunoblotting assay
• Experiment for Drug Resistance: Growth curves and transformation assay
• Mechanism Description: The missense mutation p.E768D (c.2304G>C) in gene RET cause the sensitivity of Vandetanib by aberration of the drug's therapeutic target

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

• Molecule Alteration: Missense mutation; p.L790F (c.2370G>T)
• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HEK293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• Experiment for Molecule Alteration: Immunoblotting assay
• Experiment for Drug Resistance: Growth curves and transformation assay
• Mechanism Description: The missense mutation p.L790F (c.2370G>T) in gene RET cause the sensitivity of Vandetanib by aberration of the drug's therapeutic target

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

• Molecule Alteration: Missense mutation; p.Y791F (c.2372A>T)
• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HEK293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• Experiment for Molecule Alteration: Immunoblotting assay
• Experiment for Drug Resistance: Growth curves and transformation assay
• Mechanism Description: The missense mutation p.Y791F (c.2372A>T) in gene RET cause the sensitivity of Vandetanib by aberration of the drug's therapeutic target

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

• Molecule Alteration: Missense mutation; p.A883F (c.2647_2648delGCinsTT)
• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HEK293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• Experiment for Molecule Alteration: Immunoblotting assay
• Experiment for Drug Resistance: Growth curves and transformation assay
• Mechanism Description: The missense mutation p.A883F (c.2647_2648delGCinsTT) in gene RET cause the sensitivity of Vandetanib by aberration of the drug's therapeutic target

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

• Molecule Alteration: Missense mutation; p.S891A (c.2671T>G)
• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HEK293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• Experiment for Molecule Alteration: Immunoblotting assay
• Experiment for Drug Resistance: Growth curves and transformation assay
• Mechanism Description: The missense mutation p.S891A (c.2671T>G) in gene RET cause the sensitivity of Vandetanib by aberration of the drug's therapeutic target

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

• Molecule Alteration: Missense mutation; p.M918T (c.2753T>C)
• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HEK293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• Experiment for Molecule Alteration: Immunoblotting assay
• Experiment for Drug Resistance: Growth curves and transformation assay
• Mechanism Description: The missense mutation p.M918T (c.2753T>C) in gene RET cause the sensitivity of Vandetanib by aberration of the drug's therapeutic target

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Tyrosine-protein kinase ABL1 (ABL1) [3]

• Molecule Alteration: Missense mutation; p.V299L (c.895G>C)
• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: Ph+ALL cells; N.A.; .; N.A.
• Mechanism Description: The missense mutation p.V299L (c.895G>C) in gene ABL1 cause the sensitivity of Vandetanib by aberration of the drug's therapeutic target

Lung cancer [ICD-11: 2C25]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Epidermal growth factor receptor (EGFR) [4]

• Molecule Alteration: Missense mutation; p.L858R (c.2573T>G)
• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: H1975 cells; Lung; Homo sapiens (Human); CVCL_1511
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: HCC827 cells; Lung; Homo sapiens (Human); CVCL_2063
• In Vitro Model: H1650 cells; Pleural effusion; Homo sapiens (Human); CVCL_4V01
• In Vitro Model: Calu-6 cells; Lung; Homo sapiens (Human); CVCL_0236
• In Vivo Model: Mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The missense mutation p.L858R (c.2573T>G) in gene EGFR cause the sensitivity of Vandetanib by aberration of the drug's therapeutic target

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: Proto-oncogene tyrosine-protein kinase receptor Ret (RET) [5]

• Molecule Alteration: Missense mutation; p.M918T (c.2753T>C)
• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: SW1271 cells; Lung; Homo sapiens (Human); CVCL_1716
• In Vitro Model: H1048 cells; Pleural effusion; Homo sapiens (Human); CVCL_1453
• Experiment for Molecule Alteration: Western blotting analysis; Sanger sequencing; qPCR
• Experiment for Drug Resistance: MTT assay

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Epidermal growth factor receptor (EGFR) [6]

• Molecule Alteration: IF-deletion; p.E746_A750delELREA (c.2236_2250del15)
• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: LOVO cells; Colon; Homo sapiens (Human); CVCL_0399
• In Vitro Model: A431 cells; Skin; Homo sapiens (Human); CVCL_0037
• In Vitro Model: PC-14 cells; Lung; Homo sapiens (Human); CVCL_1640
• In Vitro Model: WiDR cells; Colon; Homo sapiens (Human); CVCL_2760
• In Vitro Model: SkBR3 cells; Breast; Homo sapiens (Human); CVCL_0033
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: PC9 cells; Lung; Homo sapiens (Human); CVCL_B260
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The if-deletion p.E746_A750delELREA (c.2236_2250del15) in gene EGFR cause the sensitivity of Vandetanib by unusual activation of pro-survival pathway.

Thyroid cancer [ICD-11: 2D10]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Proto-oncogene tyrosine-protein kinase receptor Ret (RET) [7]

• Molecule Alteration: Missense mutation; p.C634W (c.1902C>G)
• Sensitive Disease: Thyroid gland cancer [ICD-11: 2D10.0]
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Proto-oncogene tyrosine-protein kinase receptor Ret (RET) [7]

• Molecule Alteration: Missense mutation; p.M918T (c.2753T>C)
• Sensitive Disease: Thyroid gland cancer [ICD-11: 2D10.0]
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: PCR

Multiple endocrine neoplasia [ICD-11: 2F7A]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Proto-oncogene tyrosine-protein kinase receptor Ret (RET) [1]

• 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) [1]

• 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: 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
• Ref 2: Disease associated mutations at valine 804 in the RET receptor tyrosine kinase confer resistance to selective kinase inhibitorsOncogene. 2004 Aug 12;23(36):6056-63. doi: 10.1038/sj.onc.1207810.
• Ref 3: Exploiting Temporal Collateral Sensitivity in Tumor Clonal EvolutionCell. 2016 Mar 24;165(1):234-246. doi: 10.1016/j.cell.2016.01.045. Epub 2016 Feb 25.
• Ref 4: Combined vascular endothelial growth factor receptor and epidermal growth factor receptor (EGFR) blockade inhibits tumor growth in xenograft models of EGFR inhibitor resistanceClin Cancer Res. 2009 May 15;15(10):3484-94. doi: 10.1158/1078-0432.CCR-08-2904. Epub 2009 May 15.
• Ref 5: RET mutation and expression in small-cell lung cancerJ Thorac Oncol. 2014 Sep;9(9):1316-23. doi: 10.1097/JTO.0000000000000234.
• Ref 6: Small in-frame deletion in the epidermal growth factor receptor as a target for ZD6474Cancer Res. 2004 Dec 15;64(24):9101-4. doi: 10.1158/0008-5472.CAN-04-2360.
• Ref 7: Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trialJ Clin Oncol. 2012 Jan 10;30(2):134-41. doi: 10.1200/JCO.2011.35.5040. Epub 2011 Oct 24.