Drug Information

Drug (ID: DG01190) and It's Reported Resistant Information

• Name: Midostaurin
• Synonyms: Midostaurin; PKC412; 120685-11-2; Cgp 41251; PKC-412; 4'-N-Benzoylstaurosporine; Benzoylstaurosporine; CGP-41251; RYDAPT; PKC 412; UNII-ID912S5VON; N-Benzoylstaurosporine; ID912S5VON; CHEMBL608533; CHEBI:63452; N-[(5S,6R,7R,9R)-6-methoxy-5-methyl-14-oxo-6,7,8,9,15,16-hexahydro-5H,14H-5,9-epoxy-4b,9a,15-triazadibenzo[b,h]cyclonona[1,2,3,4-jkl]cyclopenta[e]-as-indacen-7-yl]-N-methylbenzamide; Cgp 41 251; Midostaurin [USAN:INN]; CGP 41231; NSC-656576; Rydapt (TN); Midostaurin(PKC412); 4-N-benzoylstaurosporine; Staurosporine, N-Benzoyl; NVP-PKC412; Midostaurin (JAN/USAN/INN); GTPL5702; SCHEMBL8295379; HMS3229K17; EX-A1741; BDBM50326053; CGP-41521; MFCD00871372; NSC800791; s8064; AKOS024457372; ZINC100013130; CCG-101288; CS-3331; DB06595; NSC 656576; NSC-800791; NCGC00241102-01; NCGC00241102-02; NCGC00241102-05; NCGC00484987-03; AC-31929; Benzamide, N-(2,3,9,10,11,12-hexahydro-9-methoxy-8-methyl-1-oxo-8,12-epoxy-1H,8H-2,7b,12a-triazadibenzo(a,g)cyclonona(cde)trinden-10-yl)-N-methyl-, (8alpha,9beta,10beta,12alpha)-; HY-10230; N-((9S,10R,11R,13R)-10-methoxy-9-methyl-1-oxo-2,3,10,11,12,13-hexahydro-9,13-epoxy-1H,9H-diindolo(1,2,3-gh:3',2',1'-lm)pyrrolo(3,4-j)(1,7)benzodiazonin-11-yl)-N-methylbenzamide; C71714; D05029; J-004379; Q6842945; BRD-K13646352-001-01-2; [9S-(9 ,10 ,11 ,13 )]-N-(2,3,10,11,12,13-Hexahydro-10-methoxy-9-methyl-1-oxo-9,13-epoxy-1H,9H-diindolo[1,2,3-gh:3',2',1'-lm]pyrrolo[3,4-j][1,7]benzodiazonin-11-yl)-N-methylbenzamide; Benzamide, N-((9S,10R,11R,13R)-2,3,9,10,11,12-hexahydro-10-methoxy-9-methyl-1-oxo-9,13-epoxy-1H,9H-diindolo(1,2,3-gh:3',2',1'-lm)pyrrolo(3,4-j)(1,7)benzodiazonin-11-yl)-N-methyl-; N-[(2S,3R,4R,6R)-3-methoxy-2-methyl-16-oxo-29-oxa-1,7,17-triazaoctacyclo[12.12.2.1^{2,6}.0^{7,28}.0^{8,13}.0^{15,19}.0^{20,27}.0^{21,26}]nonacosa-8,10,12,14(28),15(19),20(27),21,23,25-nonaen-4-yl]-N-methylbenzamide; N-[(2S,3R,4R,6R)-3-methoxy-2-methyl-16-oxo-29-oxa-1,7,17-triazaoctacyclo[12.12.2.12,6.07,28.08,13.015,19.020,27.021,26]nonacosa-8,10,12,14,19,21,23,25,27-nonaen-4-yl]-N-methylbenzamide
• Indication:
  In total 5 Indication(s)
  Acute myeloid leukaemia [ICD-11: 2A60]; Approved; [1]
  Acute myeloid leukaemia [ICD-11: 2A60]; Approved; [1]
  Chronic myelomonocytic leukaemia [ICD-11: 2A40]; Approved; [1]
  Colorectal cancer [ICD-11: 2B91]; Approved; [1]
  Systemic mastocytosis [ICD-11: 2A21]; Approved; [1]
• Drug Resistance Disease(s):
  Disease(s) with Clinically Reported Resistance for This Drug (1 diseases)
  Solid tumour/cancer [ICD-11: 2A00-2F9Z]; [2]
  Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (1 diseases)
  Acute myeloid leukemia [ICD-11: 2A60]; [1]
• Target: Fms-like tyrosine kinase 3 (FLT-3); FLT3_HUMAN; [1]
• Target: Protein kinase C gamma (PRKCG); KPCG_HUMAN; [1]
• Formula: C35H30N4O4
• IsoSMILES: C[C@@]12[C@@H]([C@@H](C[C@@H](O1)N3C4=CC=CC=C4C5=C6C(=C7C8=CC=CC=C8N2C7=C53)CNC6=O)N(C)C(=O)C9=CC=CC=C9)OC
• InChI: 1S/C35H30N4O4/c1-35-32(42-3)25(37(2)34(41)19-11-5-4-6-12-19)17-26(43-35)38-23-15-9-7-13-20(23)28-29-22(18-36-33(29)40)27-21-14-8-10-16-24(21)39(35)31(27)30(28)38/h4-16,25-26,32H,17-18H2,1-3H3,(H,36,40)/t25-,26-,32-,35+/m1/s1
• InChIKey: BMGQWWVMWDBQGC-IIFHNQTCSA-N
• PubChem CID: 9829523
• ChEBI ID: CHEBI:63452
• TTD Drug ID: D07NVU
• VARIDT ID: DR01370
• INTEDE ID: DR1090
• DrugBank ID: DB06595

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

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

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [2]

• Molecule Alteration: Missense mutation; p.S451F (c.1352C>T)
• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Bone marrow; N.A.
• Experiment for Molecule Alteration: Western blotting analysis
• Mechanism Description: The missense mutation p.S451F (c.1352C>T) in gene FLT3 cause the resistance of Midostaurin by unusual activation of pro-survival pathway

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Platelet-derived growth factor receptor alpha (PDGFRA) [3]

• Molecule Alteration: Missense mutation; p.D842V (c.2525A>T)
• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: THP-1 cells; Blood; Homo sapiens (Human); CVCL_0006
• In Vitro Model: Kasumi-1 cells; Peripheral blood; Homo sapiens (Human); CVCL_0589
• In Vitro Model: H1703 cells; Lung; Homo sapiens (Human); CVCL_1490
• In Vitro Model: HCT-116 cells; Colon; Homo sapiens (Human); N.A.
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: HMC-1.2 cells; Blood; Homo sapiens (Human); CVCL_H205
• In Vitro Model: P815 cells; N.A.; Mus musculus (Mouse); CVCL_2154
• In Vitro Model: MV-4-11 cells; Peripheral blood; Homo sapiens (Human); CVCL_0064
• In Vitro Model: HMC-1.1 cells; Peripheral blood; Homo sapiens (Human); CVCL_H206
• In Vitro Model: EOL1 cells; Peripheral blood; Homo sapiens (Human); CVCL_0258
• In Vitro Model: CHO-K1 cells; Ovary; Cricetulus griseus (Chinese hamster) (Cricetulus barabensis griseus); CVCL_0214
• In Vivo Model: Female Hsd:Athymic Nude-Foxn1nu nude mouse xenograft model; Mus musculus
• Experiment for Drug Resistance: IC50 assay

Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [4]

• Molecule Alteration: IF-deletion; p.I836delI (c.2508_2510delCAT)
• 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
• Experiment for Molecule Alteration: Immunoblotting analysis
• Mechanism Description: The if-deletion p.I836delI (c.2508_2510delCAT) in gene FLT3 cause the sensitivity of Midostaurin by aberration of the drug's therapeutic target.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [5]

• Molecule Alteration: Missense mutation; p.D816V (c.2447A>T)
• 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: M230 cells; Skin; Homo sapiens (Human); CVCL_D749
• Experiment for Molecule Alteration: PCR
• Experiment for Drug Resistance: CellTiter-Glo assay; IC50 assay

Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [2]

• Molecule Alteration: Missense mutation; p.Y572C (c.1715A>G)
• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Bone marrow; N.A.
• Experiment for Molecule Alteration: Western blotting analysis
• Mechanism Description: The missense mutation p.Y572C (c.1715A>G) in gene FLT3 cause the sensitivity of Midostaurin by unusual activation of pro-survival pathway

Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [2]

• Molecule Alteration: Missense mutation; p.V592G (c.1775T>G)
• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Bone marrow; N.A.
• Experiment for Molecule Alteration: Western blotting analysis
• Mechanism Description: The missense mutation p.V592G (c.1775T>G) in gene FLT3 cause the sensitivity of Midostaurin by unusual activation of pro-survival pathway

Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [2]

• Molecule Alteration: Missense mutation; p.R834Q (c.2501G>A)
• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Bone marrow; N.A.
• Experiment for Molecule Alteration: Western blotting analysis
• Mechanism Description: The missense mutation p.R834Q (c.2501G>A) in gene FLT3 cause the sensitivity of Midostaurin by unusual activation of pro-survival pathway

Mastocytosis [ICD-11: 2A21]

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]

• Molecule Alteration: Missense mutation; p.V560G (c.1679T>G)
• Sensitive Disease: Mast cell neoplasm [ICD-11: 2A21.1]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: THP-1 cells; Blood; Homo sapiens (Human); CVCL_0006
• In Vitro Model: Kasumi-1 cells; Peripheral blood; Homo sapiens (Human); CVCL_0589
• In Vitro Model: H1703 cells; Lung; Homo sapiens (Human); CVCL_1490
• In Vitro Model: HCT-116 cells; Colon; Homo sapiens (Human); N.A.
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: HMC-1.2 cells; Blood; Homo sapiens (Human); CVCL_H205
• In Vitro Model: P815 cells; N.A.; Mus musculus (Mouse); CVCL_2154
• In Vitro Model: MV-4-11 cells; Peripheral blood; Homo sapiens (Human); CVCL_0064
• In Vitro Model: HMC-1.1 cells; Peripheral blood; Homo sapiens (Human); CVCL_H206
• In Vitro Model: EOL1 cells; Peripheral blood; Homo sapiens (Human); CVCL_0258
• In Vitro Model: CHO-K1 cells; Ovary; Cricetulus griseus (Chinese hamster) (Cricetulus barabensis griseus); CVCL_0214
• In Vivo Model: Female Hsd:Athymic Nude-Foxn1nu nude mouse xenograft model; Mus musculus
• Experiment for Drug Resistance: IC50 assay

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [6]

• Molecule Alteration: Missense mutation; p.S476I (c.1427G>T)
• Sensitive Disease: Mast cell leukaemia [ICD-11: 2A21.2]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Bone marrow; N.A.
• Experiment for Molecule Alteration: Histologic and immunophenotypic analysis
• Experiment for Drug Resistance: Examination of bone marrow smears assay

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

• Molecule Alteration: Missense mutation; p.D816Y (c.2446G>T)
• Sensitive Disease: Mast cell neoplasm [ICD-11: 2A21.1]
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [7]

• Molecule Alteration: Missense mutation; p.D816V (c.2447A>T)
• Sensitive Disease: Systemic mastocytosis [ICD-11: 2A21.3]
• Experimental Note: Identified from the Human Clinical Data

Acute myeloid leukemia [ICD-11: 2A60]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Ras-related C3 botulinum toxin substrate 1 (RAC1) [1]

• Molecule Alteration: Function; Activation
• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HEK293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• In Vitro Model: 786-O cells; Kidney; Homo sapiens (Human); CVCL_1051
• Experiment for Molecule Alteration: RAC1 activation assay
• Experiment for Drug Resistance: CellTiter-Glo Luminescent Cell Viability Assay; Flow cytometric analysis
• Mechanism Description: Midostaurin resistance can be overcome by a combination of midostaruin, the BCL-2 inhibitor venetoclax and the RAC1 inhibitor Eht1864 in midostaurin-resistant AML cell lines and primary samples, providing the first evidence of a potential new treatment approach to eradicate FLT3-ITD + AML.

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) [8]

• Molecule Alteration: Missense mutation; p.Y842C (c.2525A>G)
• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Bone marrow; N.A.
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The missense mutation p.Y842C (c.2525A>G) in gene FLT3 cause the sensitivity of Midostaurin by aberration of the drug's therapeutic target

Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [9]

• Molecule Alteration: Missense mutation; p.D835Y (c.2503G>T)
• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Bone marrow; N.A.
• Mechanism Description: The missense mutation p.D835Y (c.2503G>T) in gene FLT3 cause the sensitivity of Midostaurin by aberration of the drug's therapeutic target

Unusual Activation of Pro-survival Pathway (UAPP)

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

• Molecule Alteration: Missense mutation; p.N822K (c.2466T>G)
• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: THP-1 cells; Blood; Homo sapiens (Human); CVCL_0006
• In Vitro Model: Kasumi-1 cells; Peripheral blood; Homo sapiens (Human); CVCL_0589
• In Vitro Model: H1703 cells; Lung; Homo sapiens (Human); CVCL_1490
• In Vitro Model: HCT-116 cells; Colon; Homo sapiens (Human); N.A.
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: HMC-1.2 cells; Blood; Homo sapiens (Human); CVCL_H205
• In Vitro Model: P815 cells; N.A.; Mus musculus (Mouse); CVCL_2154
• In Vitro Model: MV-4-11 cells; Peripheral blood; Homo sapiens (Human); CVCL_0064
• In Vitro Model: HMC-1.1 cells; Peripheral blood; Homo sapiens (Human); CVCL_H206
• In Vitro Model: EOL1 cells; Peripheral blood; Homo sapiens (Human); CVCL_0258
• In Vitro Model: CHO-K1 cells; Ovary; Cricetulus griseus (Chinese hamster) (Cricetulus barabensis griseus); CVCL_0214
• In Vivo Model: Female Hsd:Athymic Nude-Foxn1nu nude mouse xenograft model; Mus musculus
• Experiment for Drug Resistance: IC50 assay

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [10]

• Molecule Alteration: Missense mutation; p.D816V (c.2447A>T)
• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• 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

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) [10]

• Molecule Alteration: Missense mutation; p.D835Y (c.2503G>T)
• Sensitive Disease: Hematologic Cancer [ICD-11: MG24.Y]
• 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) [10]

• Molecule Alteration: Missense mutation; p.D816V (c.2447A>T)
• Sensitive Disease: Hematologic Cancer [ICD-11: MG24.Y]
• 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: Actin cytoskeleton deregulation confers midostaurin resistance in FLT3-mutant acute myeloid leukemia .Commun Biol. 2021 Jun 25;4(1):799. doi: 10.1038/s42003-021-02215-w. 10.1038/s42003-021-02215-w
• Ref 2: Identification of driver and passenger mutations of FLT3 by high-throughput DNA sequence analysis and functional assessment of candidate allelesCancer Cell. 2007 Dec;12(6):501-13. doi: 10.1016/j.ccr.2007.11.005.
• Ref 3: Ripretinib (DCC-2618) Is a Switch Control Kinase Inhibitor of a Broad Spectrum of Oncogenic and Drug-Resistant KIT and PDGFRA VariantsCancer Cell. 2019 May 13;35(5):738-751.e9. doi: 10.1016/j.ccell.2019.04.006.
• Ref 4: Uniform sensitivity of FLT3 activation loop mutants to the tyrosine kinase inhibitor midostaurinBlood. 2007 Dec 15;110(13):4476-9. doi: 10.1182/blood-2007-07-101238. Epub 2007 Sep 7.
• Ref 5: ATP-Competitive Inhibitors Midostaurin and Avapritinib Have Distinct Resistance Profiles in Exon 17-Mutant KITCancer Res. 2019 Aug 15;79(16):4283-4292. doi: 10.1158/0008-5472.CAN-18-3139. Epub 2019 Jul 3.
• Ref 6: Chronic mast cell leukemia (MCL) with KIT S476I: a rare entity defined by leukemic expansion of mature mast cells and absence of organ damageAnn Hematol. 2015 Feb;94(2):223-31. doi: 10.1007/s00277-014-2207-9. Epub 2014 Sep 11.
• Ref 7: Efficacy and Safety of Midostaurin in Advanced Systemic MastocytosisN Engl J Med. 2016 Jun 30;374(26):2530-41. doi: 10.1056/NEJMoa1513098.
• Ref 8: Identification of a novel activating mutation (Y842C) within the activation loop of FLT3 in patients with acute myeloid leukemia (AML)Blood. 2005 Jan 1;105(1):335-40. doi: 10.1182/blood-2004-02-0660. Epub 2004 Sep 2.
• Ref 9: Phase IIB trial of oral Midostaurin (PKC412), the FMS-like tyrosine kinase 3 receptor (FLT3) and multi-targeted kinase inhibitor, in patients with acute myeloid leukemia and high-risk myelodysplastic syndrome with either wild-type or mutated FLT3J Clin Oncol. 2010 Oct 1;28(28):4339-45. doi: 10.1200/JCO.2010.28.9678. Epub 2010 Aug 23.
• Ref 10: 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.