Drug Information

Drug (ID: DG01267) and It's Reported Resistant Information

• Name: Gilteritinib
• Synonyms: Gilteritinib; 1254053-43-4; ASP2215; ASP-2215; Xospata; UNII-66D92MGC8M; ASP 2215; 6-Ethyl-3-((3-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-amino)-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazine-2-carboxamide; 66D92MGC8M; Gilteritinib HCl; 6-Ethyl-3-((3-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazine-2-carboxamide; 2-Pyrazinecarboxamide, 6-ethyl-3-((3-methoxy-4-(4-(4-methyl-1-piperazinyl)-1-piperidinyl)phenyl)amino)-5-((tetrahydro-2H-pyran-4-yl)amino)-; 6-ethyl-3-[[3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl]amino]-5-(oxan-4-ylamino)pyrazine-2-carboxamide; 6-ethyl-3-[3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]anilino]-5-(oxan-4-ylamino)pyrazine-2-carboxamide; Gilteritinib [USAN:INN]; gilteritinibum; 2-Pyrazinecarboxamide, 6-ethyl-3-[[3-methoxy-4-[4-(4-methyl-1-piperazinyl)-1-piperidinyl]phenyl]amino]-5-[(tetrahydro-2H-pyran-4-yl)amino]-; C6F; Gilteritinib(ASP2215); Gilteritinib (USAN/INN); Gilteritinib (ASP2215); Gilteritinib (ASP-2215); SCHEMBL282229; GTPL8708; CHEMBL3301622; CHEBI:145372; BDBM144315; C29H44N8O3; BCP28756; EX-A2775; 3694AH; MFCD28144685; NSC787846; NSC787854; NSC788454; NSC800106; s7754; ZINC113476229; CCG-270016; CS-3885; DB12141; NSC-787846; NSC-787854; NSC-788454; NSC-800106; SB16988; NCGC00481652-01; NCGC00481652-02; AC-29030; AS-35199; BG166434; HY-12432; QC-11768; DB-108103; A14411; D10709; A901674; US8969336, 547; US8969336, 577; Q27077802; 6-ethyl-3-((3-methoxy-4-(4-(4-methyl-1-piperazinyl)-1-piperidinyl)phenyl)amino)-5-((tetrahydro-2H-pyran-4-yl)amino)-2-pyrazinecarboxamide; 6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide; 6-Ethyl-3-[3-methoxy-4-[4-(4-methylpiperazine-1-yl)piperidino]anilino]-5-[(tetrahydro-2H-pyran-4-yl)amino]pyrazine-2-carboxamide; 6-ethyl-3-{3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]anilino}-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide; 6-ethyl-3-{3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]anilino}-5-[(oxan-4-yl)amino]pyrazine-2-carboxamide
• Indication:
  In total 2 Indication(s)
  Acute myeloid leukaemia [ICD-11: 2A60]; Approved; [1]
  Acute myeloid leukaemia [ICD-11: 2A60]; Approved; [1]
• Drug Resistance Disease(s):
  Disease(s) with Clinically Reported Resistance for This Drug (1 diseases)
  Acute myeloid leukemia [ICD-11: 2A60]; [1]
  Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (1 diseases)
  Acute myeloid leukemia [ICD-11: 2A60]; [2]
• Target: Fms-like tyrosine kinase 3 (FLT-3); FLT3_HUMAN; [1]
• Target: Tyrosine-protein kinase UFO (AXL); UFO_HUMAN; [1]
• Formula: C29H44N8O3
• IsoSMILES: CCC1=C(N=C(C(=N1)C(=O)N)NC2=CC(=C(C=C2)N3CCC(CC3)N4CCN(CC4)C)OC)NC5CCOCC5
• InChI: 1S/C29H44N8O3/c1-4-23-28(31-20-9-17-40-18-10-20)34-29(26(33-23)27(30)38)32-21-5-6-24(25(19-21)39-3)37-11-7-22(8-12-37)36-15-13-35(2)14-16-36/h5-6,19-20,22H,4,7-18H2,1-3H3,(H2,30,38)(H2,31,32,34)
• InChIKey: GYQYAJJFPNQOOW-UHFFFAOYSA-N
• PubChem CID: 49803313
• ChEBI ID: CHEBI:145372
• TTD Drug ID: D04KZY
• VARIDT ID: DR00358
• INTEDE ID: DR0772
• DrugBank ID: DB12141

Type(s) of Resistant Mechanism of This Drug

  ADTT: Aberration of the Drug's Therapeutic Target

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Their Corresponding Diseases

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

Acute myeloid leukemia [ICD-11: 2A60]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Beclin-1 (BECN1) [2]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell autophagy; Inhibition; hsa04140
• In Vitro Model: MV4-11/Gilteritinib cells; myeloid; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: In gilteritinib-resistant AML cells, autophagy-related markers, mRFP-GFP-LC3 signals and autophagosome numbers were significantly enhanced. Autophagy inhibitor 3-MA could suppress gilteritinib resistance in AML cells. RNF38 knockdown inhibited gilteritinib resistance and autophagy in AML cells. Mechanistically, RNF38 reduced LMX1A expression by inducing its ubiquitination. RNF38 overexpression reversed the inhibitory effect of LMX1A on gilteritinib resistance and autophagy in AML cells, as well as AML tumor growth in vivo, while these effects could be abolished by proteasome inhibitor MG132.

Key Molecule: Beclin-1 (BECN1) [2]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell autophagy; Inhibition; hsa04140
• In Vitro Model: MOLM-13/Gilteritinib cells; myeloid; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: In gilteritinib-resistant AML cells, autophagy-related markers, mRFP-GFP-LC3 signals and autophagosome numbers were significantly enhanced. Autophagy inhibitor 3-MA could suppress gilteritinib resistance in AML cells. RNF38 knockdown inhibited gilteritinib resistance and autophagy in AML cells. Mechanistically, RNF38 reduced LMX1A expression by inducing its ubiquitination. RNF38 overexpression reversed the inhibitory effect of LMX1A on gilteritinib resistance and autophagy in AML cells, as well as AML tumor growth in vivo, while these effects could be abolished by proteasome inhibitor MG134.

Key Molecule: Microtubule-associated protein 1 light chain 3-II/I (LC3-II/LC3-I) [2]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell autophagy; Inhibition; hsa04140
• In Vitro Model: MV4-11/Gilteritinib cells; myeloid; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: In gilteritinib-resistant AML cells, autophagy-related markers, mRFP-GFP-LC3 signals and autophagosome numbers were significantly enhanced. Autophagy inhibitor 3-MA could suppress gilteritinib resistance in AML cells. RNF38 knockdown inhibited gilteritinib resistance and autophagy in AML cells. Mechanistically, RNF38 reduced LMX1A expression by inducing its ubiquitination. RNF38 overexpression reversed the inhibitory effect of LMX1A on gilteritinib resistance and autophagy in AML cells, as well as AML tumor growth in vivo, while these effects could be abolished by proteasome inhibitor MG133.

Key Molecule: Microtubule-associated protein 1 light chain 3-II/I (LC3-II/LC3-I) [2]

• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell autophagy; Inhibition; hsa04140
• In Vitro Model: MOLM-13/Gilteritinib cells; myeloid; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: In gilteritinib-resistant AML cells, autophagy-related markers, mRFP-GFP-LC3 signals and autophagosome numbers were significantly enhanced. Autophagy inhibitor 3-MA could suppress gilteritinib resistance in AML cells. RNF38 knockdown inhibited gilteritinib resistance and autophagy in AML cells. Mechanistically, RNF38 reduced LMX1A expression by inducing its ubiquitination. RNF38 overexpression reversed the inhibitory effect of LMX1A on gilteritinib resistance and autophagy in AML cells, as well as AML tumor growth in vivo, while these effects could be abolished by proteasome inhibitor MG135.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [3]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Missense mutation; p.D816V (c.2447A>T)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: MV4-11 cells; Peripheral blood; Homo sapiens (Human); CVCL_0064
• In Vitro Model: MOLM14 cells; Peripheral blood; Homo sapiens (Human); CVCL_7916
• In Vivo Model: Female NCr-nude mouse model; Mus musculus
• Experiment for Drug Resistance: CellTiter-Glo assay; IC50 assay

Key Molecule: E3 ubiquitin-protein ligase RNF38 (RNF38) [2]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell autophagy; Inhibition; hsa04140
• In Vitro Model: MV4-11/Gilteritinib si-RNF38 cells; myeloid; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot assay; qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: In gilteritinib-resistant AML cells, autophagy-related markers, mRFP-GFP-LC3 signals and autophagosome numbers were significantly enhanced. Autophagy inhibitor 3-MA could suppress gilteritinib resistance in AML cells. RNF38 knockdown inhibited gilteritinib resistance and autophagy in AML cells. Mechanistically, RNF38 reduced LMX1A expression by inducing its ubiquitination. RNF38 overexpression reversed the inhibitory effect of LMX1A on gilteritinib resistance and autophagy in AML cells, as well as AML tumor growth in vivo, while these effects could be abolished by proteasome inhibitor MG136.

Key Molecule: E3 ubiquitin-protein ligase RNF38 (RNF38) [2]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell autophagy; Inhibition; hsa04140
• In Vitro Model: MOLM-13/Gilteritinib si-RNF38 cells; myeloid; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot assay; qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: In gilteritinib-resistant AML cells, autophagy-related markers, mRFP-GFP-LC3 signals and autophagosome numbers were significantly enhanced. Autophagy inhibitor 3-MA could suppress gilteritinib resistance in AML cells. RNF38 knockdown inhibited gilteritinib resistance and autophagy in AML cells. Mechanistically, RNF38 reduced LMX1A expression by inducing its ubiquitination. RNF38 overexpression reversed the inhibitory effect of LMX1A on gilteritinib resistance and autophagy in AML cells, as well as AML tumor growth in vivo, while these effects could be abolished by proteasome inhibitor MG137.

Hematologic cancer [ICD-11: 2B3Z]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [3]

• Sensitive Disease: Hematologic Cancer [ICD-11: MG24.Y]
• Molecule Alteration: Missense mutation; p.D835Y (c.2503G>T)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: MV4-11 cells; Peripheral blood; Homo sapiens (Human); CVCL_0064
• In Vitro Model: MOLM14 cells; Peripheral blood; Homo sapiens (Human); CVCL_7916
• In Vivo Model: Female NCr-nude mouse model; Mus musculus
• Experiment for Drug Resistance: CellTiter-Glo assay; IC50 assay

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [3]

• Sensitive Disease: Hematologic Cancer [ICD-11: MG24.Y]
• Molecule Alteration: Missense mutation; p.D816V (c.2447A>T)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: MV4-11 cells; Peripheral blood; Homo sapiens (Human); CVCL_0064
• In Vitro Model: MOLM14 cells; Peripheral blood; Homo sapiens (Human); CVCL_7916
• In Vivo Model: Female NCr-nude mouse model; Mus musculus
• Experiment for Drug Resistance: CellTiter-Glo assay; IC50 assay

References

• Ref 1: The AML microenvironment catalyzes a stepwise evolution to gilteritinib resistance .Cancer Cell. 2021 Jul 12;39(7):999-1014.e8. doi: 10.1016/j.ccell.2021.06.003. Epub 2021 Jun 24. 10.1016/j.ccell.2021.06.003
• Ref 2: RNF38 promotes gilteritinib resistance in acute myeloid leukemia via inducing autophagy by regulating ubiquitination of LMX1A. Cell Biol Toxicol. 2024 Nov 28;40(1):105.
• Ref 3: Comparison of effects of midostaurin, crenolanib, quizartinib, gilteritinib, sorafenib and BLU-285 on oncogenic mutants of KIT, CBL and FLT3 in haematological malignanciesBr J Haematol. 2019 Nov;187(4):488-501. doi: 10.1111/bjh.16092. Epub 2019 Jul 15.