Drug Information

Drug (ID: DG01617) and It's Reported Resistant Information

• Name: Brigatinib
• Synonyms: Brigatinib; 1197953-54-0; ALUNBRIG; AP-26113; UNII-HYW8DB273J; Brigatinib (AP-26113); HYW8DB273J; AP 26113; (2-((5-chloro-2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide; 5-chloro-4-N-(2-dimethylphosphorylphenyl)-2-N-[2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl]pyrimidine-2,4-diamine; 2,4-Pyrimidinediamine, 5-chloro-N4-(2-(dimethylphosphinyl)phenyl)-N2-(2-methoxy-4-(4-(4-methyl-1-piperazinyl)-1-piperidinyl)phenyl)-; 2,4-Pyrimidinediamine, 5-chloro-N4-[2-(dimethylphosphinyl)phenyl]-N2-[2-methoxy-4-[4-(4-methyl-1-piperazinyl)-1-piperidinyl]phenyl]-; 5-Chloro-N~4~-[2-(Dimethylphosphoryl)phenyl]-N~2~-{2-Methoxy-4-[4-(4-Methylpiperazin-1-Yl)piperidin-1-Yl]phenyl}pyrimidine-2,4-Diamine; Brigatinib [USAN]; Brigatiib; Alunbrig (TN); 5-Chloro-N4-(2-(dimethylphosphoryl)phenyl)-N2-(2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)pyrimidine-2,4-diamine; 5-chloro-N4-[2-(dimethylphosphoryl)phenyl]-N2-{2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}pyrimidine-2,4-diamine; 6GY; Brigatinib (JAN/USAN); Brigatinib [USAN:INN]; Brigatinib; AP26113; Brigatinib (AP26113); GTPL7741; CHEMBL3545311; SCHEMBL11916361; EX-A775; AMY10294; BCP17214; BDBM50185140; MFCD29472221; NSC784728; NSC787457; AKOS030257612; ZINC148723177; CS-4278; DB12267; NSC-784728; NSC-787457; SB40412; compound 11q [PMID: 27144831]; NCGC00483924-01; (2-((5-Chloro-2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethyl-,delta5-phosphanone; 5-Chloro-N4-(2-(dimethylphosphoryl)phenyl)-N2-(2-methoxy-4-(4-(4-methylpiperazin-1- yl)piperidin-1-yl)phenyl)pyrimidine-2,4-diamine; 5-chloro-N4-[2-(dimethylphosphinyl)phenyl]-N2-[2-methoxy-4-[4-(4-methyl-1-piperazinyl)-1-piperidinyl]phenyl]-2,4-Pyrimidinediamine; AC-29958; AS-75176; HY-12857; DB-118419; FT-0700112; S8229; J3.535.964H; D10866; Q27456393
• Indication:
  In total 2 Indication(s)
  Small-cell lung cancer [ICD-11: 2C25]; Approved; [1]
  Triple negative breast cancer [ICD-11: 2C60-2C6Y]; Approved; [1]
• Drug Resistance Disease(s):
  Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (2 diseases)
  Lung cancer [ICD-11: 2C25]; [1]
  Solid tumour/cancer [ICD-11: 2A00-2F9Z]; [2]
• Target: Cyclin-dependent kinase 4 (CDK4); CDK4_HUMAN; [3]
• Target: Cyclin-dependent kinase 6 (CDK6); CDK6_HUMAN; [3]
• Formula: 8
• IsoSMILES: CN1CCN(CC1)C2CCN(CC2)C3=CC(=C(C=C3)NC4=NC=C(C(=N4)NC5=CC=CC=C5P(=O)(C)C)Cl)OC
• InChI: InChI=1S/C29H39ClN7O2P/c1-35-15-17-37(18-16-35)21-11-13-36(14-12-21)22-9-10-24(26(19-22)39-2)33-29-31-20-23(30)28(34-29)32-25-7-5-6-8-27(25)40(3,4)38/h5-10,19-21H,11-18H2,1-4H3,(H2,31,32,33,34)
• InChIKey: AILRADAXUVEEIR-UHFFFAOYSA-N
• PubChem CID: 68165256
• TTD Drug ID: D0AP9E
• VARIDT ID: DR0228
• INTEDE ID: DR00368
• DrugBank ID: DB12267

Type(s) of Resistant Mechanism of This Drug

  ADTT: Aberration of the Drug's Therapeutic Target

  EADR: Epigenetic Alteration of DNA, RNA or Protein

Drug Resistance Data Categorized by Their Corresponding Diseases

ICD-02: Benign/in-situ/malignant neoplasm

Brain cancer [ICD-11: 2A00]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: ALK tyrosine kinase receptor (ALK) [4]

• Molecule Alteration: Missense mutation; p.F1174V (c.3520T>G)
• Sensitive Disease: Neuroblastoma [ICD-11: 2A00.11]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: IMR-32 cells; Abdomen; Homo sapiens (Human); CVCL_0346
• In Vitro Model: PC12 cells; Adrenal gland; Rattus norvegicus (Rat); CVCL_0481
• In Vitro Model: CLB-PE cells; Brain; Homo sapiens (Human); CVCL_9534
• In Vitro Model: CLB-GE cells; Bone marrow; Homo sapiens (Human); CVCL_9530
• In Vitro Model: CLB-BAR cells; Brain; Homo sapiens (Human); CVCL_9519
• In Vivo Model: Female Balbc/nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Immunohistochemistry assay
• Experiment for Drug Resistance: Resazurin disc test assay
• Mechanism Description: Anaplastic lymphoma kinase (ALK) is a tyrosine kinase receptor which has been implicated in numerous solid and hematologic cancers. Brigatinib is an effective inhibitor of ALK kinase activity in ALK addicted neuroblastoma

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: ALK tyrosine kinase receptor (ALK) [2]

• Molecule Alteration: Missense mutation; p.G1202R (c.3604G>A)
• Resistant 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
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Thymidine Incorporation assay

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: ALK tyrosine kinase receptor (ALK) [4]

• Molecule Alteration: Missense mutation; p.G1128A (c.3383G>C)
• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: IMR-32 cells; Abdomen; Homo sapiens (Human); CVCL_0346
• In Vitro Model: CLB-GE cells; Bone marrow; Homo sapiens (Human); CVCL_9530
• In Vitro Model: CLB-BAR cells; Brain; Homo sapiens (Human); CVCL_9519
• In Vivo Model: Female Balbc/nude mouse xenograft model; Mus musculus
• Mechanism Description: The missense mutation p.G1128A (c.3383G>C) in gene ALK cause the sensitivity of Brigatinib by aberration of the drug's therapeutic target

Key Molecule: ALK tyrosine kinase receptor (ALK) [4]

• Molecule Alteration: Missense mutation; p.I1171N (c.3512T>A)
• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: IMR-32 cells; Abdomen; Homo sapiens (Human); CVCL_0346
• In Vitro Model: CLB-GE cells; Bone marrow; Homo sapiens (Human); CVCL_9530
• In Vitro Model: CLB-BAR cells; Brain; Homo sapiens (Human); CVCL_9519
• In Vivo Model: Female Balbc/nude mouse xenograft model; Mus musculus
• Mechanism Description: The missense mutation p.I1171N (c.3512T>A) in gene ALK cause the sensitivity of Brigatinib by aberration of the drug's therapeutic target

Key Molecule: ALK tyrosine kinase receptor (ALK) [4]

• Molecule Alteration: Missense mutation; p.F1174L (c.3520T>C)
• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: IMR-32 cells; Abdomen; Homo sapiens (Human); CVCL_0346
• In Vitro Model: CLB-GE cells; Bone marrow; Homo sapiens (Human); CVCL_9530
• In Vitro Model: CLB-BAR cells; Brain; Homo sapiens (Human); CVCL_9519
• In Vivo Model: Female Balbc/nude mouse xenograft model; Mus musculus
• Mechanism Description: The missense mutation p.F1174L (c.3520T>C) in gene ALK cause the sensitivity of Brigatinib by aberration of the drug's therapeutic target

Key Molecule: ALK tyrosine kinase receptor (ALK) [4]

• Molecule Alteration: Missense mutation; p.R1192P (c.3575G>C)
• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: IMR-32 cells; Abdomen; Homo sapiens (Human); CVCL_0346
• In Vitro Model: CLB-GE cells; Bone marrow; Homo sapiens (Human); CVCL_9530
• In Vitro Model: CLB-BAR cells; Brain; Homo sapiens (Human); CVCL_9519
• In Vivo Model: Female Balbc/nude mouse xenograft model; Mus musculus
• Mechanism Description: The missense mutation p.R1192P (c.3575G>C) in gene ALK cause the sensitivity of Brigatinib by aberration of the drug's therapeutic target

Key Molecule: ALK tyrosine kinase receptor (ALK) [4]

• Molecule Alteration: Missense mutation; p.F1245C (c.3734T>G)
• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: IMR-32 cells; Abdomen; Homo sapiens (Human); CVCL_0346
• In Vitro Model: CLB-GE cells; Bone marrow; Homo sapiens (Human); CVCL_9530
• In Vitro Model: CLB-BAR cells; Brain; Homo sapiens (Human); CVCL_9519
• In Vivo Model: Female Balbc/nude mouse xenograft model; Mus musculus
• Mechanism Description: The missense mutation p.F1245C (c.3734T>G) in gene ALK cause the sensitivity of Brigatinib by aberration of the drug's therapeutic target

Key Molecule: ALK tyrosine kinase receptor (ALK) [4]

• Molecule Alteration: Missense mutation; p.R1275Q (c.3824G>A)
• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: IMR-32 cells; Abdomen; Homo sapiens (Human); CVCL_0346
• In Vitro Model: CLB-GE cells; Bone marrow; Homo sapiens (Human); CVCL_9530
• In Vitro Model: CLB-BAR cells; Brain; Homo sapiens (Human); CVCL_9519
• In Vivo Model: Female Balbc/nude mouse xenograft model; Mus musculus
• Mechanism Description: The missense mutation p.R1275Q (c.3824G>A) in gene ALK cause the sensitivity of Brigatinib by aberration of the drug's therapeutic target

Key Molecule: ALK tyrosine kinase receptor (ALK) [4]

• Molecule Alteration: Missense mutation; p.Y1278S (c.3833A>C)
• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: IMR-32 cells; Abdomen; Homo sapiens (Human); CVCL_0346
• In Vitro Model: CLB-GE cells; Bone marrow; Homo sapiens (Human); CVCL_9530
• In Vitro Model: CLB-BAR cells; Brain; Homo sapiens (Human); CVCL_9519
• In Vivo Model: Female Balbc/nude mouse xenograft model; Mus musculus
• Mechanism Description: The missense mutation p.Y1278S (c.3833A>C) in gene ALK cause the sensitivity of Brigatinib by aberration of the drug's therapeutic target

Key Molecule: ALK tyrosine kinase receptor (ALK) [2]

• Molecule Alteration: Missense mutation; p.G1269A (c.3806G>C)
• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: IMR-32 cells; Abdomen; Homo sapiens (Human); CVCL_0346
• In Vitro Model: PC12 cells; Adrenal gland; Rattus norvegicus (Rat); CVCL_0481
• In Vitro Model: CLB-PE cells; Brain; Homo sapiens (Human); CVCL_9534
• In Vitro Model: CLB-GE cells; Bone marrow; Homo sapiens (Human); CVCL_9530
• In Vitro Model: CLB-BAR cells; Brain; Homo sapiens (Human); CVCL_9519
• In Vivo Model: Female Balbc/nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Resazurin assay

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: Epidermal growth factor receptor (EGFR) [5]

• Molecule Alteration: IF-deletion; p.E746_A750delELREA (c.2236_2250del15)
• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: U937 cells; Blood; Homo sapiens (Human); CVCL_0007
• In Vitro Model: H23 cells; Lung; Homo sapiens (Human); CVCL_1547
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: SUP-M2 cells; Colon; Homo sapiens (Human); CVCL_2209
• In Vitro Model: KARPAS-299 cells; Peripheral blood; Homo sapiens (Human); CVCL_1324
• In Vitro Model: SU-DHL-1 cells; Pleural effusion; Homo sapiens (Human); CVCL_0538
• In Vitro Model: L-82 cells; Pleural effusion; Homo sapiens (Human); CVCL_2098
• In Vitro Model: HCC78 cells; Pleural effusion; Homo sapiens (Human); CVCL_2061
• In Vitro Model: H838 cells; Lymph node; Homo sapiens (Human); CVCL_1594
• In Vitro Model: H-4-II-E cells; Liver; Rattus norvegicus (Rat); CVCL_0284
• In Vitro Model: H358 cells; Lung; Homo sapiens (Human); CVCL_1559
• In Vitro Model: H2228 cells; Lung; Homo sapiens (Human); CVCL_1543
• In Vitro Model: DEL cells; Pleural effusion; Homo sapiens (Human); CVCL_1170
• In Vivo Model: SCID beige mouse PDX model; Mus musculus
• Experiment for Drug Resistance: Promega assay
• Mechanism Description: Non-small cell lung cancers (NSCLCs) harboring ALK gene rearrangements (ALK+) typically become resistant to the first-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) crizotinib through development of secondary resistance mutations in ALK or disease progression in the brain. Mutations that confer resistance to second-generation ALK TKIs ceritinib and alectinib have also been identified. Brigatinib is the only TKI to maintain substantial activity against the most recalcitrant ALK resistance mutation, G1202R. The unique, potent, and pan-ALK mutant activity of brigatinib could be rationalized by structural analyses.

Key Molecule: Epidermal growth factor receptor (EGFR) [5]

• Molecule Alteration: Missense mutation; p.L858R (c.2573T>G)
• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: U937 cells; Blood; Homo sapiens (Human); CVCL_0007
• In Vitro Model: H23 cells; Lung; Homo sapiens (Human); CVCL_1547
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: SUP-M2 cells; Colon; Homo sapiens (Human); CVCL_2209
• In Vitro Model: KARPAS-299 cells; Peripheral blood; Homo sapiens (Human); CVCL_1324
• In Vitro Model: SU-DHL-1 cells; Pleural effusion; Homo sapiens (Human); CVCL_0538
• In Vitro Model: L-82 cells; Pleural effusion; Homo sapiens (Human); CVCL_2098
• In Vitro Model: HCC78 cells; Pleural effusion; Homo sapiens (Human); CVCL_2061
• In Vitro Model: H838 cells; Lymph node; Homo sapiens (Human); CVCL_1594
• In Vitro Model: H-4-II-E cells; Liver; Rattus norvegicus (Rat); CVCL_0284
• In Vitro Model: H358 cells; Lung; Homo sapiens (Human); CVCL_1559
• In Vitro Model: H2228 cells; Lung; Homo sapiens (Human); CVCL_1543
• In Vitro Model: DEL cells; Pleural effusion; Homo sapiens (Human); CVCL_1170
• In Vivo Model: SCID beige mouse PDX model; Mus musculus
• Experiment for Drug Resistance: Promega assay
• Mechanism Description: Non-small cell lung cancers (NSCLCs) harboring ALK gene rearrangements (ALK+) typically become resistant to the first-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) crizotinib through development of secondary resistance mutations in ALK or disease progression in the brain. Mutations that confer resistance to second-generation ALK TKIs ceritinib and alectinib have also been identified. Brigatinib is the only TKI to maintain substantial activity against the most recalcitrant ALK resistance mutation, G1202R. The unique, potent, and pan-ALK mutant activity of brigatinib could be rationalized by structural analyses.

Lung cancer [ICD-11: 2C25]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Proto-oncogene c-Ros (ROS1) [1]

• Molecule Alteration: Missense mutation; p.G2032R (c.6094G>A)
• Resistant Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• Experiment for Molecule Alteration: Western blotting analysis; Conformational analysis
• Experiment for Drug Resistance: CellTiter-96 AQueous One assay

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: ALK tyrosine kinase receptor (ALK) [3]

• Molecule Alteration: Missense mutation; p.V1180L (c.3538G>C)
• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: PC9 cells; Lung; Homo sapiens (Human); CVCL_B260
• In Vitro Model: NSCLC cells; Lung; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CellTiter-Glo assay

Key Molecule: ALK tyrosine kinase receptor (ALK) [6]

• Molecule Alteration: Missense mutation; p.L1196M (c.3586C>A)
• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Experimental Note: Identified from the Human Clinical Data

References

• Ref 1: Structural insight into selectivity and resistance profiles of ROS1 tyrosine kinase inhibitorsProc Natl Acad Sci U S A. 2015 Sep 29;112(39):E5381-90. doi: 10.1073/pnas.1515281112. Epub 2015 Sep 8.
• Ref 2: Activity of second-generation ALK inhibitors against crizotinib-resistant mutants in an NPM-ALK model compared to EML4-ALKCancer Med. 2015 Jul;4(7):953-65. doi: 10.1002/cam4.413. Epub 2015 Feb 26.
• Ref 3: Two novel ALK mutations mediate acquired resistance to the next-generation ALK inhibitor alectinib. Clin Cancer Res. 2014 Nov 15;20(22):5686-96. doi: 10.1158/1078-0432.CCR-14-1511. Epub 2014 Sep 16.
• Ref 4: Brigatinib, an anaplastic lymphoma kinase inhibitor, abrogates activity and growth in ALK-positive neuroblastoma cells, Drosophila and miceOncotarget. 2016 May 17;7(20):29011-22. doi: 10.18632/oncotarget.8508.
• Ref 5: The Potent ALK Inhibitor Brigatinib (AP26113) Overcomes Mechanisms of Resistance to First- and Second-Generation ALK Inhibitors in Preclinical ModelsClin Cancer Res. 2016 Nov 15;22(22):5527-5538. doi: 10.1158/1078-0432.CCR-16-0569. Epub 2016 Oct 25.
• Ref 6: Activity of brigatinib (BRG) in crizotinib (CRZ)-resistant ALK+ NSCLC patients (pts) according to ALK plasma mutation status.