Drug Information

Drug (ID: DG01577) and It's Reported Resistant Information

• Name: Flumatinib
• Synonyms: Flumatinib; 895519-90-1; HHGV678; HH-GV678; Flumatinib free base; flumbatinib; UNII-R4009Y24AI; HHGV-678; R4009Y24AI; 895519-90-1 (free base); 4-[(4-methylpiperazin-1-yl)methyl]-N-[6-methyl-5-[(4-pyridin-3-ylpyrimidin-2-yl)amino]pyridin-3-yl]-3-(trifluoromethyl)benzamide; HHGV678 mesylate; BenzaMide, 4-[(4-Methyl-1-piperazinyl)Methyl]-N-[6-Methyl-5-[[4-(3-pyridinyl)-2-pyriMidinyl]aMino]-3-pyridinyl]-3-(trifluoroMethyl)-; N-(6-methyl-5-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)pyridin-3-yl)-4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzamide; HH-GV-678; Hansoh Xinfu; flumatinib (pseudo INN); GTPL9913; SCHEMBL4883843; CHEMBL3545413; DTXSID60237779; BCP23797; EX-A3572; VKB51990; BDBM50529313; NSC830368; ZINC68244727; CS-5550; DB11904; NSC-830368; SB17192; NCGC00378614-01; 4-(4-Methylpiperazin-1-ylmethyl)-N-(6-methyl-5-(4-pyridin-3-ylpyrimidin-2-ylamino)pyridin-3-yl)-3-trifluoromethylbenzamide; DA-33625; HY-13904; FT-0739882; Q27287759; N-[5-[[4-(3-Pyridinyl)pyrimidine-2-yl]amino]-6-methylpyridine-3-yl]-3-(trifluoromethyl)-4-[(4-methylpiperazine-1-yl)methyl]benzamide
• Indication:
  In total 3 Indication(s)
  leukaemia [ICD-11: 2A60-2B33]; Phase 2; [1]
  Multiple myeloma [ICD-11: 2A83]; Phase 2; [1]
  Solid tumour/cancer [ICD-11: 2A00-2F9Z]; Phase 2; [1]
• Drug Resistance Disease(s):
  Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (2 diseases)
  Chronic myeloid leukemia [ICD-11: 2A20]; [2]
  Solid tumour/cancer [ICD-11: 2A00-2F9Z]; [1]
  Disease(s) with Clinically Reported Resistance for This Drug (1 diseases)
  Solid tumour/cancer [ICD-11: 2A00-2F9Z]; [1]
• Target: RAC-alpha serine/threonine-protein kinase (AKT1); AKT1_HUMAN; [1]
• Formula: 7
• IsoSMILES: CC1=C(C=C(C=N1)NC(=O)C2=CC(=C(C=C2)CN3CCN(CC3)C)C(F)(F)F)NC4=NC=CC(=N4)C5=CN=CC=C5
• InChI: InChI=1S/C29H29F3N8O/c1-19-26(38-28-34-9-7-25(37-28)21-4-3-8-33-16-21)15-23(17-35-19)36-27(41)20-5-6-22(24(14-20)29(30,31)32)18-40-12-10-39(2)11-13-40/h3-9,14-17H,10-13,18H2,1-2H3,(H,36,41)(H,34,37,38)
• InChIKey: BJCJYEYYYGBROF-UHFFFAOYSA-N
• PubChem CID: 46848036
• TTD Drug ID: D02NXM
• DrugBank ID: DB11904

Type(s) of Resistant Mechanism of This Drug

  ADTT: Aberration of the Drug's Therapeutic Target

  IDUE: Irregularity in Drug Uptake and Drug Efflux

  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: Mast/stem cell growth factor receptor Kit (KIT) [1]

• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Molecule Alteration: Duplication; p.I571_D579 (c.1711_1737)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: 32D cells; Bone marrow; Homo sapiens (Human); CVCL_0118
• In Vivo Model: Female Balb/cA-nu/nu mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The duplication p.I571_D579 (c.1711_1737) in gene KIT cause the resistance of Flumatinib by aberration of the drug's therapeutic target.

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [1]

• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Molecule Alteration: Missense mutation; p.D816Y (c.2446G>T)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: IL-3-dependent murine hematopoietic cells; Blood; Mus musculus (Mouse); CVCL_2015
• In Vitro Model: IL-3-dependent murine hematopoietic cells; Blood; Mus musculus (Mouse); CVCL_2015
• In Vivo Model: Female Balb/cA-nu/nu mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [1]

• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Molecule Alteration: Missense mutation; p.D816V (c.2447A>T)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: IL-3-dependent murine hematopoietic cells; Blood; Mus musculus (Mouse); CVCL_2015
• In Vitro Model: IL-3-dependent murine hematopoietic cells; Blood; Mus musculus (Mouse); CVCL_2015
• In Vivo Model: Female Balb/cA-nu/nu mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [1]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Molecule Alteration: Missense mutation; p.N822K (c.2466T>G)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: 32D cells; Bone marrow; Homo sapiens (Human); CVCL_0118
• In Vivo Model: Female Balb/cA-nu/nu mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The missense mutation p.N822K (c.2466T>G) in gene KIT cause the sensitivity of Flumatinib by aberration of the drug's therapeutic target

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [1]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Molecule Alteration: Complex-indel; p.T417_D419delinsI (c.1249_1257delinsATC)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: 32D cells; Bone marrow; Homo sapiens (Human); CVCL_0118
• In Vivo Model: Female Balb/cA-nu/nu mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The complex-indel p.T417_D419delinsI (c.1249_1257delinsATC) in gene KIT cause the sensitivity of Flumatinib by aberration of the drug's therapeutic target.

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [1]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Molecule Alteration: Duplication; p.A502_Y503 (c.1504_1509)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: 32D cells; Bone marrow; Homo sapiens (Human); CVCL_0118
• In Vivo Model: Female Balb/cA-nu/nu mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The duplication p.A502_Y503 (c.1504_1509) in gene KIT cause the sensitivity of Flumatinib by aberration of the drug's therapeutic target.

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [1]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Molecule Alteration: Missense mutation; p.V559D (c.1676T>A)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: 32D cells; Bone marrow; Homo sapiens (Human); CVCL_0118
• In Vivo Model: Female Balb/cA-nu/nu mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The missense mutation p.V559D (c.1676T>A) in gene KIT cause the sensitivity of Flumatinib by aberration of the drug's therapeutic target

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [1]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Molecule Alteration: IF-deletion; p.V559_V560delVV (c.1676_1681delTTGTTG)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: 32D cells; Bone marrow; Homo sapiens (Human); CVCL_0118
• In Vivo Model: Female Balb/cA-nu/nu mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The if-deletion p.V559_V560delVV (c.1676_1681delTTGTTG) in gene KIT cause the sensitivity of Flumatinib by aberration of the drug's therapeutic target.

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [1]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Molecule Alteration: Missense mutation; p.D816H (c.2446G>C)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: 32D cells; Bone marrow; Homo sapiens (Human); CVCL_0118
• In Vivo Model: Female Balb/cA-nu/nu mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The missense mutation p.D816H (c.2446G>C) in gene KIT cause the sensitivity of Flumatinib by aberration of the drug's therapeutic target

Chronic myeloid leukemia [ICD-11: 2A20]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug resistance-associated protein 1 (MRP1) [2]

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: K562/FLM cells; Blood; Homo sapiens (Human); CVCL_E7CM
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: Through cellular experimentation, we explored the resistance mechanisms, which indicated that K562/FLM cells evade flumatinib cytotoxicity by enhancing autophagy, increasing the expression of membrane transport proteins, particularly P-glycoprotein, ABCC1 and ABCC4, as well as enhancing phosphorylation of p-EGFR, p-ERK and p-STAT3 proteins.

Key Molecule: ATP-binding cassette sub-family C4 (ABCC4) [2]

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: K562/FLM cells; Blood; Homo sapiens (Human); CVCL_E7CM
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: Through cellular experimentation, we explored the resistance mechanisms, which indicated that K562/FLM cells evade flumatinib cytotoxicity by enhancing autophagy, increasing the expression of membrane transport proteins, particularly P-glycoprotein, ABCC1 and ABCC4, as well as enhancing phosphorylation of p-EGFR, p-ERK and p-STAT3 proteins.

Key Molecule: P-glycoprotein (ABCB1) [2]

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: K562/FLM cells; Blood; Homo sapiens (Human); CVCL_E7CM
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: Through cellular experimentation, we explored the resistance mechanisms, which indicated that K562/FLM cells evade flumatinib cytotoxicity by enhancing autophagy, increasing the expression of membrane transport proteins, particularly P-glycoprotein, ABCC1 and ABCC4, as well as enhancing phosphorylation of p-EGFR, p-ERK and p-STAT3 proteins.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Signal transducer activator transcription 3 (STAT3) [2]

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Molecule Alteration: Phosphorylation; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: EGFR/STAT3/ERK signalling pathway; Regulation; N.A.
• In Vitro Model: K562/FLM cells; Blood; Homo sapiens (Human); CVCL_E7CM
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: Through cellular experimentation, we explored the resistance mechanisms, which indicated that K562/FLM cells evade flumatinib cytotoxicity by enhancing autophagy, increasing the expression of membrane transport proteins, particularly P-glycoprotein, ABCC1 and ABCC4, as well as enhancing phosphorylation of p-EGFR, p-ERK and p-STAT3 proteins.

Key Molecule: Mitogen-activated protein kinase (MAPK) [2]

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Molecule Alteration: Phosphorylation; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: EGFR/STAT3/ERK signalling pathway; Regulation; N.A.
• In Vitro Model: K562/FLM cells; Blood; Homo sapiens (Human); CVCL_E7CM
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: Through cellular experimentation, we explored the resistance mechanisms, which indicated that K562/FLM cells evade flumatinib cytotoxicity by enhancing autophagy, increasing the expression of membrane transport proteins, particularly P-glycoprotein, ABCC1 and ABCC4, as well as enhancing phosphorylation of p-EGFR, p-ERK and p-STAT3 proteins.

Key Molecule: Oncogenic epidermal growth factor receptor (EGFR) [2]

• Resistant Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Molecule Alteration: Phosphorylation; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: EGFR/STAT3/ERK signalling pathway; Regulation; N.A.
• In Vitro Model: K562/FLM cells; Blood; Homo sapiens (Human); CVCL_E7CM
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: Through cellular experimentation, we explored the resistance mechanisms, which indicated that K562/FLM cells evade flumatinib cytotoxicity by enhancing autophagy, increasing the expression of membrane transport proteins, particularly P-glycoprotein, ABCC1 and ABCC4, as well as enhancing phosphorylation of p-EGFR, p-ERK and p-STAT3 proteins.

References

• Ref 1: Flumatinib, a selective inhibitor of BCR-ABL/PDGFR/KIT, effectively overcomes drug resistance of certain KIT mutantsCancer Sci. 2014 Jan;105(1):117-25. doi: 10.1111/cas.12320. Epub 2014 Jan 4.
• Ref 2: Overcoming flumatinib resistance in chronic myeloid leukaemia: Insights into cellular mechanisms and ivermectin's therapeutic potential. J Cell Mol Med. 2024 Jul;28(14):e18539.