Identification
NameMidostaurin
Accession NumberDB06595
TypeSmall Molecule
GroupsApproved
Description

Midostaurin (as Rydapt) is a multitarget kinase inhibitor for the treatment for adult patients with newly diagnosed acute myeloid leukemia (AML) who have a specific genetic mutation called FLT3. It was initially characterized as a potential broad-spectrum antineoplastic agent, with activity toward diverse solid and hematopoietic tumors [4]. It was approved on April 28, 2017 and has shown to increase the overall survival rate in patients with AML as an adjunct therapy along with chemotherapeutic agents.

Structure
Thumb
Synonyms
4'-N-benzoylstaurosporine
External IDs CGP 41251 / CGP-41251 / NVP-PKC412 / PKC 412 / PKC-412
Product Ingredients Not Available
Approved Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
RydaptCapsule, liquid filled25 mg/1OralNovartis2017-04-28Not applicableUs
RydaptCapsule25 mgOralNovartisNot applicableNot applicableCanada
Approved Generic Prescription ProductsNot Available
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International BrandsNot Available
Brand mixturesNot Available
Categories
UNIIID912S5VON
CAS number120685-11-2
WeightAverage: 570.649
Monoisotopic: 570.226705462
Chemical FormulaC35H30N4O4
InChI KeyBMGQWWVMWDBQGC-IIFHNQTCSA-N
InChI
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
IUPAC Name
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(13),9,11,14(28),15(19),20(27),21(26),22,24-nonaen-4-yl]-N-methylbenzamide
SMILES
CO[[email protected]@H]1[[email protected]@H](C[[email protected]]2O[[email protected]]1(C)N1C3=C(C=CC=C3)C3=C1C1=C(C4=C(C=CC=C4)N21)C1=C3CNC1=O)N(C)C(=O)C1=CC=CC=C1
Pharmacology
Indication

Investigated for use/treatment in adult patients with high-risk acute myeloid leukemia (AML) who are FLT3 mutation-positive, agressive systemic mastocytosis (ASM), systemic mastocytosis with associated hematological neoplasm (SM-AHN), or mast cell leukemia (MCL).

Structured Indications
Pharmacodynamics

It targets multiple WT and mutated kinases that, when activated, constitutively stimulate aberrant signalling cascades that lead to malignancies such as AML and ASM. Alternative pharmacodynamic effect of midostaurin in prolonging QTc intervals was not clinically significant in patients with advanced SM or AML when compared to placebo. Midostaurin is therapeutically beneficial as a combination therapy for patients undergoing chemotherapy.

Mechanism of action

It potently inhibits multiple receptor tyrosine kinases. Midostaurin and its major active metabolites CGP62221 and CGP52421 inhibit the activity of protein kinase C alpha (PKCalpha), VEGFR2, KIT, PDGFR and WT and/or mutant FLT3 tyrosine kinases. Inhibition of FLT3 receptor signalling cascades induces apoptosis of target leukemia cells expressing target receptors and mast cells, in addition to its antiproliferative activity toward multiple cancer cell lines [4]. Midostaurin also interacts with organic anion transporter (OATP) 1A1 and multidrug resistance protein (MRP)-2 according to preliminary in vitro studies.

TargetKindPharmacological actionActionsOrganismUniProt ID
Protein kinase C alpha typeProteinyes
antagonist
inhibitor
HumanP17252 details
Vascular endothelial growth factor receptor 2Proteinyes
antagonist
inhibitor
HumanP35968 details
Mast/stem cell growth factor receptor KitProteinunknown
antagonist
inhibitor
HumanP10721 details
Platelet-derived growth factor receptor alphaProteinyes
antagonist
inhibitor
HumanP16234 details
Platelet-derived growth factor receptor betaProteinyes
antagonist
inhibitor
HumanP09619 details
Receptor-type tyrosine-protein kinase FLT3Proteinyes
antagonist
inhibitor
HumanP36888 details
Related Articles
Absorption

The time to reach maximum concentration ranges from 1-3 hrs in fasting patients. The maximum concentration and the time it takes to reach this concentration is reduced up to 20% in presence of a standard meal.

Volume of distribution

The Vd of midostaurin is 95.2L. The parent drug and its main metabolites (CGP62221, CGP52421) are distributed in plasma in vitro.

Protein binding

Midostaurin predominantly binds to α1-acid glycoprotein in vitro. The parent drug and its metabolites are >99.8% bound to plasma proteins in vitro.

Metabolism

Midostaurin is primarily metabolized into CGP62221 and CGP52421 via hepatic CYP3A4 enzymatic activity. The metabolism of CGP62221 takes place initially in a linear relationship whereas CGP52421 formation is an inducible process [5].

SubstrateEnzymesProduct
Midostaurin
CGP 52421Details
Midostaurin
CGP 62221Details
Route of elimination

Accounting for 95% of recovered dose eliminated through fecal excretion, 91% was determined as metabolites and 4% as unchanged parent drug. Remaining 5% of the recovered dose is eliminated via renal excretion.

Half life

Elimination half life is approximately 21 hrs for midostaurin, 32 hrs for CGP62221 and 482 hrs for CGP52421.

Clearance

The clearance values of during the initial formation of metabolites are 1.47 L/h for CGP62221 metabolite and 0.501 L/h for CGP52421. 28 days following the oral administration of midostaurin, the clearance of CGP52421 may increase up to 5.2 fold in a recommended dose of 25 mg, resulting in a 2.1- to 2.5-fold increase in total clearance of midostaurin [5].

Toxicity

In a fertility study involving female and male rats, there is evidence of reproductive toxicity including reduced sperm count and decline pregnancy rates when administering 0.01 to 0.1 times the recommended dose in humans. LD50 for oral midostaurin for mouse, rat and rabbit are 300mg/kg, 980mg/kg and 3200mg/kg, respectively [8]. Incidences of pulmonary toxicities including interstitial lung disease and pneumonitis have occured in few patients undergoing midostaurin monotherapy or combination therapy.

Affected organisms
  • Humans and other mammals
PathwaysNot Available
Pharmacogenomic Effects/ADRs Not Available
Interactions
Drug Interactions
DrugInteractionDrug group
AcetyldigitoxinAcetyldigitoxin may decrease the cardiotoxic activities of Midostaurin.Approved
BevacizumabBevacizumab may increase the cardiotoxic activities of Midostaurin.Approved, Investigational
CabazitaxelThe risk or severity of adverse effects can be increased when Cabazitaxel is combined with Midostaurin.Approved
CyclophosphamideCyclophosphamide may increase the cardiotoxic activities of Midostaurin.Approved, Investigational
DeslanosideDeslanoside may decrease the cardiotoxic activities of Midostaurin.Approved
DigitoxinDigitoxin may decrease the cardiotoxic activities of Midostaurin.Approved
DigoxinDigoxin may decrease the cardiotoxic activities of Midostaurin.Approved
DocetaxelThe risk or severity of adverse effects can be increased when Docetaxel is combined with Midostaurin.Approved, Investigational
OleandrinAnvirzel may decrease the cardiotoxic activities of Midostaurin.Experimental
OuabainOuabain may decrease the cardiotoxic activities of Midostaurin.Approved
PaclitaxelThe risk or severity of adverse effects can be increased when Paclitaxel is combined with Midostaurin.Approved, Vet Approved
TrastuzumabTrastuzumab may increase the cardiotoxic activities of Midostaurin.Approved, Investigational
Food InteractionsNot Available
References
Synthesis ReferenceNot Available
General References
  1. Fischer T, Stone RM, Deangelo DJ, Galinsky I, Estey E, Lanza C, Fox E, Ehninger G, Feldman EJ, Schiller GJ, Klimek VM, Nimer SD, Gilliland DG, Dutreix C, Huntsman-Labed A, Virkus J, Giles FJ: 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 FLT3. J Clin Oncol. 2010 Oct 1;28(28):4339-45. doi: 10.1200/JCO.2010.28.9678. Epub 2010 Aug 23. [PubMed:20733134 ]
  2. Millward MJ, House C, Bowtell D, Webster L, Olver IN, Gore M, Copeman M, Lynch K, Yap A, Wang Y, Cohen PS, Zalcberg J: The multikinase inhibitor midostaurin (PKC412A) lacks activity in metastatic melanoma: a phase IIA clinical and biologic study. Br J Cancer. 2006 Oct 9;95(7):829-34. Epub 2006 Sep 12. [PubMed:16969355 ]
  3. Gotlib J, Kluin-Nelemans HC, George TI, Akin C, Sotlar K, Hermine O, Awan FT, Hexner E, Mauro MJ, Sternberg DW, Villeneuve M, Huntsman Labed A, Stanek EJ, Hartmann K, Horny HP, Valent P, Reiter A: Efficacy and Safety of Midostaurin in Advanced Systemic Mastocytosis. N Engl J Med. 2016 Jun 30;374(26):2530-41. doi: 10.1056/NEJMoa1513098. [PubMed:27355533 ]
  4. Gallogly MM, Lazarus HM: Midostaurin: an emerging treatment for acute myeloid leukemia patients. J Blood Med. 2016 Apr 19;7:73-83. doi: 10.2147/JBM.S100283. eCollection 2016. [PubMed:27186148 ]
  5. Yin OQ, Wang Y, Schran H: A mechanism-based population pharmacokinetic model for characterizing time-dependent pharmacokinetics of midostaurin and its metabolites in human subjects. Clin Pharmacokinet. 2008;47(12):807-16. doi: 10.2165/0003088-200847120-00005. [PubMed:19026036 ]
  6. Abmole Midostaurin MSDS [Link]
  7. Alfa Aesar Midostaurin MSDS [Link]
  8. Cayman Midostaurin MSDS [Link]
External Links
ATC CodesNot Available
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelDownload (306 KB)
MSDSNot Available
Clinical Trials
Clinical Trials
PhaseStatusPurposeConditionsCount
1Active Not RecruitingTreatmentAcute Myeloid Leukaemias (AML) / Myelodysplastic Syndrome1
1Active Not RecruitingTreatmentAdenocarcinoma of the Rectum1
1CompletedTreatmentAcute Myeloid Leukaemias (AML)2
1CompletedTreatmentAcute Myeloid Leukaemias (AML) / Acute Myeloid Leukemia With Multilineage Dysplasia Following / Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities / Adult Acute Myeloid Leukemia With Del(5q) / Adult Acute Myeloid Leukemia With Inv(16)(p13;q22) / Adult Acute Myeloid Leukemia With T(15;17)(q22;q12) / Adult Acute Myeloid Leukemia With T(16;16)(p13;q22) / Adult Acute Myeloid Leukemia With T(8;21)(q22;q22) / Myelodysplastic Syndrome / Recurrent Adult Acute Myeloid Leukemia / Secondary Acute Myeloid Leukemia1
1CompletedTreatmentLeukemia, Myeloid, Acute1
1RecruitingBasic ScienceHepatic Impairment1
1RecruitingTreatmentAML and High Risk MDS1
1, 2Active Not RecruitingTreatmentUntreated Adult Acute Myeloid Leukemia1
1, 2CompletedTreatmentAcute Myeloid Leukaemias (AML) / Myelodysplastic Syndrome1
1, 2CompletedTreatmentAcute Myeloid Leukaemias (AML) / Myelodysplastic Syndromes1
1, 2CompletedTreatmentLeukemias1
1, 2TerminatedTreatmentAcute Lymphoblastic Leukaemias (ALL) / Acute Myeloid Leukaemias (AML)1
2Active Not RecruitingTreatmentAcute Myeloid Leukemia (AML) With Multilineage Dysplasia Following Myelodysplastic Syndrome, in Adults / Acute Myeloid Leukemia With Multilineage Dysplasia Following Myelodysplastic Syndrome / Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities / Adult Acute Myeloid Leukemia With Del(5q) / Adult Acute Myeloid Leukemia With Inv(16)(p13;q22) / Adult Acute Myeloid Leukemia With T(16;16)(p13;q22) / Adult Acute Myeloid Leukemia With T(8;21)(q22;q22) / AML (Adult) With 11q23 (MLL) Abnormalities / AML (Adult) With Del(5q) / AML (Adult) With Inv(16)(p13;q22) / AML (Adult) With t(16;16)(p13;q22) / AML (Adult) With t(8;21)(q22;q22) / Secondary Acute Myeloid Leukemia / Secondary AML (Adult) / Untreated Adult Acute Myeloid Leukemia / Untreated AML (Adult)1
2Active Not RecruitingTreatmentHematological Non-mast Cell Lineage Disease (AHNMD) / Malignant mast cell neoplasm / Systemic Mastocytosis, Aggressive (ASM)1
2Active Not RecruitingTreatmentLeukemias1
2Not Yet RecruitingTreatmentAcute Myeloid Leukaemias (AML)2
2Not Yet RecruitingTreatmentAcute Myeloid Leukemia With Gene Mutations / Adult Acute Myeloid Leukemia in Remission1
2RecruitingPreventionAcute Myeloid Leukaemias (AML)1
2RecruitingTreatmentAcute Myeloid Leukaemias (AML)2
2RecruitingTreatmentAcute Myeloid Leukemia With FLT3/ITD Mutation / Acute Myeloid Leukemia With Gene Mutations / FLT3 Tyrosine Kinase Domain Point Mutation / Secondary Acute Myeloid Leukemia / Untreated Adult Acute Myeloid Leukemia1
2Unknown StatusTreatmentIndolent Systemic Mastocytosis1
2, 3Not Yet RecruitingTreatmentAcute Myeloid Leukaemias (AML) / Adult Myelodysplastic Syndrome / Myelodysplastic Syndrome With Excess Blasts-2 / Untreated Adult Acute Myeloid Leukemia1
3Active Not RecruitingTreatmentLeukemias1
3Not Yet RecruitingTreatmentNewly Diagnosed FLT3 Mutated AML1
Not AvailableAvailableNot AvailableAcute Myeloid Leukemia (AML) With / FLT3 Mutation, Internal Tandem Duplication (ITD) or Tyrosine Kinase Domain (TKD)1
Not AvailableAvailableNot AvailableFLT3-Mutated Acute Myeloid Leukemia1
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage forms
FormRouteStrength
CapsuleOral25 mg
Capsule, liquid filledOral25 mg/1
PricesNot Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US8575146 No2010-12-022030-12-02Us
US7973031 No2004-10-172024-10-17Us
US8222244 No2002-10-292022-10-29Us
Properties
StateSolid
Experimental Properties
PropertyValueSource
melting point (°C)235-260Alfa Aesar MSDS
water solubility<1mg/mLAbmole MSDS
logP5.89Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0157 mg/mLALOGPS
logP4.52ALOGPS
logP5.43ChemAxon
logS-4.6ALOGPS
pKa (Strongest Acidic)13.45ChemAxon
pKa (Strongest Basic)-0.83ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count4ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area77.73 Å2ChemAxon
Rotatable Bond Count3ChemAxon
Refractivity162.61 m3·mol-1ChemAxon
Polarizability60.58 Å3ChemAxon
Number of Rings9ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET featuresNot Available
Spectra
Mass Spec (NIST)Not Available
Spectra
Spectrum TypeDescriptionSplash Key
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, NegativeNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, NegativeNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, NegativeNot Available
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as indolocarbazoles. These are polycyclic aromatic compounds containing an indole fused to a carbazole.
KingdomOrganic compounds
Super ClassOrganoheterocyclic compounds
ClassIndoles and derivatives
Sub ClassCarbazoles
Direct ParentIndolocarbazoles
Alternative ParentsPyrrolo[2,3-a]carbazoles / Pyrroloindoles / Isoindolones / Benzamides / Indoles / Benzoyl derivatives / Oxanes / Tertiary carboxylic acid amides / Heteroaromatic compounds / Pyrroles
SubstituentsIndolocarbazole / Pyrrolo[2,3-a]carbazole / Pyrroloindole / Isoindolone / Benzamide / Benzoic acid or derivatives / Isoindole or derivatives / Isoindoline / Indole / Benzoyl
Molecular FrameworkAromatic heteropolycyclic compounds
External Descriptorsbenzamides, gamma-lactam, organic heterooctacyclic compound, indolocarbazole (CHEBI:63452 )

Targets

Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
antagonistinhibitor
General Function:
Zinc ion binding
Specific Function:
Calcium-activated, phospholipid- and diacylglycerol (DAG)-dependent serine/threonine-protein kinase that is involved in positive and negative regulation of cell proliferation, apoptosis, differentiation, migration and adhesion, tumorigenesis, cardiac hypertrophy, angiogenesis, platelet function and inflammation, by directly phosphorylating targets such as RAF1, BCL2, CSPG4, TNNT2/CTNT, or activ...
Gene Name:
PRKCA
Uniprot ID:
P17252
Uniprot Name:
Protein kinase C alpha type
Molecular Weight:
76749.445 Da
References
  1. Millward MJ, House C, Bowtell D, Webster L, Olver IN, Gore M, Copeman M, Lynch K, Yap A, Wang Y, Cohen PS, Zalcberg J: The multikinase inhibitor midostaurin (PKC412A) lacks activity in metastatic melanoma: a phase IIA clinical and biologic study. Br J Cancer. 2006 Oct 9;95(7):829-34. Epub 2006 Sep 12. [PubMed:16969355 ]
Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
antagonistinhibitor
General Function:
Vascular endothelial growth factor-activated receptor activity
Specific Function:
Tyrosine-protein kinase that acts as a cell-surface receptor for VEGFA, VEGFC and VEGFD. Plays an essential role in the regulation of angiogenesis, vascular development, vascular permeability, and embryonic hematopoiesis. Promotes proliferation, survival, migration and differentiation of endothelial cells. Promotes reorganization of the actin cytoskeleton. Isoforms lacking a transmembrane domai...
Gene Name:
KDR
Uniprot ID:
P35968
Uniprot Name:
Vascular endothelial growth factor receptor 2
Molecular Weight:
151525.555 Da
References
  1. Millward MJ, House C, Bowtell D, Webster L, Olver IN, Gore M, Copeman M, Lynch K, Yap A, Wang Y, Cohen PS, Zalcberg J: The multikinase inhibitor midostaurin (PKC412A) lacks activity in metastatic melanoma: a phase IIA clinical and biologic study. Br J Cancer. 2006 Oct 9;95(7):829-34. Epub 2006 Sep 12. [PubMed:16969355 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
antagonistinhibitor
General Function:
Transmembrane receptor protein tyrosine kinase activity
Specific Function:
Tyrosine-protein kinase that acts as cell-surface receptor for the cytokine KITLG/SCF and plays an essential role in the regulation of cell survival and proliferation, hematopoiesis, stem cell maintenance, gametogenesis, mast cell development, migration and function, and in melanogenesis. In response to KITLG/SCF binding, KIT can activate several signaling pathways. Phosphorylates PIK3R1, PLCG1...
Gene Name:
KIT
Uniprot ID:
P10721
Uniprot Name:
Mast/stem cell growth factor receptor Kit
Molecular Weight:
109863.655 Da
References
  1. Millward MJ, House C, Bowtell D, Webster L, Olver IN, Gore M, Copeman M, Lynch K, Yap A, Wang Y, Cohen PS, Zalcberg J: The multikinase inhibitor midostaurin (PKC412A) lacks activity in metastatic melanoma: a phase IIA clinical and biologic study. Br J Cancer. 2006 Oct 9;95(7):829-34. Epub 2006 Sep 12. [PubMed:16969355 ]
Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
antagonistinhibitor
General Function:
Vascular endothelial growth factor-activated receptor activity
Specific Function:
Tyrosine-protein kinase that acts as a cell-surface receptor for PDGFA, PDGFB and PDGFC and plays an essential role in the regulation of embryonic development, cell proliferation, survival and chemotaxis. Depending on the context, promotes or inhibits cell proliferation and cell migration. Plays an important role in the differentiation of bone marrow-derived mesenchymal stem cells. Required for...
Gene Name:
PDGFRA
Uniprot ID:
P16234
Uniprot Name:
Platelet-derived growth factor receptor alpha
Molecular Weight:
122668.46 Da
References
  1. Millward MJ, House C, Bowtell D, Webster L, Olver IN, Gore M, Copeman M, Lynch K, Yap A, Wang Y, Cohen PS, Zalcberg J: The multikinase inhibitor midostaurin (PKC412A) lacks activity in metastatic melanoma: a phase IIA clinical and biologic study. Br J Cancer. 2006 Oct 9;95(7):829-34. Epub 2006 Sep 12. [PubMed:16969355 ]
Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
antagonistinhibitor
General Function:
Vascular endothelial growth factor binding
Specific Function:
Tyrosine-protein kinase that acts as cell-surface receptor for homodimeric PDGFB and PDGFD and for heterodimers formed by PDGFA and PDGFB, and plays an essential role in the regulation of embryonic development, cell proliferation, survival, differentiation, chemotaxis and migration. Plays an essential role in blood vessel development by promoting proliferation, migration and recruitment of peri...
Gene Name:
PDGFRB
Uniprot ID:
P09619
Uniprot Name:
Platelet-derived growth factor receptor beta
Molecular Weight:
123966.895 Da
References
  1. Millward MJ, House C, Bowtell D, Webster L, Olver IN, Gore M, Copeman M, Lynch K, Yap A, Wang Y, Cohen PS, Zalcberg J: The multikinase inhibitor midostaurin (PKC412A) lacks activity in metastatic melanoma: a phase IIA clinical and biologic study. Br J Cancer. 2006 Oct 9;95(7):829-34. Epub 2006 Sep 12. [PubMed:16969355 ]
Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
antagonistinhibitor
General Function:
Vascular endothelial growth factor-activated receptor activity
Specific Function:
Tyrosine-protein kinase that acts as cell-surface receptor for the cytokine FLT3LG and regulates differentiation, proliferation and survival of hematopoietic progenitor cells and of dendritic cells. Promotes phosphorylation of SHC1 and AKT1, and activation of the downstream effector MTOR. Promotes activation of RAS signaling and phosphorylation of downstream kinases, including MAPK1/ERK2 and/or...
Gene Name:
FLT3
Uniprot ID:
P36888
Uniprot Name:
Receptor-type tyrosine-protein kinase FLT3
Molecular Weight:
112902.51 Da
References
  1. Millward MJ, House C, Bowtell D, Webster L, Olver IN, Gore M, Copeman M, Lynch K, Yap A, Wang Y, Cohen PS, Zalcberg J: The multikinase inhibitor midostaurin (PKC412A) lacks activity in metastatic melanoma: a phase IIA clinical and biologic study. Br J Cancer. 2006 Oct 9;95(7):829-34. Epub 2006 Sep 12. [PubMed:16969355 ]
  2. Gallogly MM, Lazarus HM: Midostaurin: an emerging treatment for acute myeloid leukemia patients. J Blood Med. 2016 Apr 19;7:73-83. doi: 10.2147/JBM.S100283. eCollection 2016. [PubMed:27186148 ]

Enzymes

1. Cytochrome p450 3A subfamily
Kind
Protein group
Organism
Human
Pharmacological action
unknown
Actions
substrateinhibitorinducer
References
  1. He H, Tran P, Gu H, Tedesco V, Zhang J, Lin W, Gatlik E, Klein K, Heimbach T: Midostaurin, a Novel Protein Kinase Inhibitor for the Treatment of Acute Myelogenous Leukemia: Insights from Human Absorption, Metabolism, and Excretion Studies of a BDDCS II Drug. Drug Metab Dispos. 2017 May;45(5):540-555. doi: 10.1124/dmd.116.072744. Epub 2017 Mar 7. [PubMed:28270565 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
inhibitorinducer
General Function:
Oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen
Specific Function:
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. Most active in catalyzing 2-hydroxylation. Caffeine is metabolized primarily by cytochrome CYP1A2 in the liver through an initial N...
Gene Name:
CYP1A2
Uniprot ID:
P05177
Uniprot Name:
Cytochrome P450 1A2
Molecular Weight:
58293.76 Da
References
  1. He H, Tran P, Gu H, Tedesco V, Zhang J, Lin W, Gatlik E, Klein K, Heimbach T: Midostaurin, a Novel Protein Kinase Inhibitor for the Treatment of Acute Myelogenous Leukemia: Insights from Human Absorption, Metabolism, and Excretion Studies of a BDDCS II Drug. Drug Metab Dispos. 2017 May;45(5):540-555. doi: 10.1124/dmd.116.072744. Epub 2017 Mar 7. [PubMed:28270565 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
inducer
General Function:
Steroid hydroxylase activity
Specific Function:
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. Acts as a 1,4-cineole 2-exo-monooxygenase.
Gene Name:
CYP2B6
Uniprot ID:
P20813
Uniprot Name:
Cytochrome P450 2B6
Molecular Weight:
56277.81 Da
References
  1. He H, Tran P, Gu H, Tedesco V, Zhang J, Lin W, Gatlik E, Klein K, Heimbach T: Midostaurin, a Novel Protein Kinase Inhibitor for the Treatment of Acute Myelogenous Leukemia: Insights from Human Absorption, Metabolism, and Excretion Studies of a BDDCS II Drug. Drug Metab Dispos. 2017 May;45(5):540-555. doi: 10.1124/dmd.116.072744. Epub 2017 Mar 7. [PubMed:28270565 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
inhibitorinducer
General Function:
Steroid hydroxylase activity
Specific Function:
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. In the epoxidation of arachidonic acid it generates only 14,15- and 11,12-cis-epoxyeicosatrienoic acids. It is the principal enzyme...
Gene Name:
CYP2C8
Uniprot ID:
P10632
Uniprot Name:
Cytochrome P450 2C8
Molecular Weight:
55824.275 Da
References
  1. He H, Tran P, Gu H, Tedesco V, Zhang J, Lin W, Gatlik E, Klein K, Heimbach T: Midostaurin, a Novel Protein Kinase Inhibitor for the Treatment of Acute Myelogenous Leukemia: Insights from Human Absorption, Metabolism, and Excretion Studies of a BDDCS II Drug. Drug Metab Dispos. 2017 May;45(5):540-555. doi: 10.1124/dmd.116.072744. Epub 2017 Mar 7. [PubMed:28270565 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
inhibitorinducer
General Function:
Steroid hydroxylase activity
Specific Function:
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. This enzyme contributes to the wide pharmacokinetics variability of the metabolism of drugs such as S-warfarin, diclofenac, phenyto...
Gene Name:
CYP2C9
Uniprot ID:
P11712
Uniprot Name:
Cytochrome P450 2C9
Molecular Weight:
55627.365 Da
References
  1. He H, Tran P, Gu H, Tedesco V, Zhang J, Lin W, Gatlik E, Klein K, Heimbach T: Midostaurin, a Novel Protein Kinase Inhibitor for the Treatment of Acute Myelogenous Leukemia: Insights from Human Absorption, Metabolism, and Excretion Studies of a BDDCS II Drug. Drug Metab Dispos. 2017 May;45(5):540-555. doi: 10.1124/dmd.116.072744. Epub 2017 Mar 7. [PubMed:28270565 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
inhibitorinducer
General Function:
Steroid hydroxylase activity
Specific Function:
Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and imipramine.
Gene Name:
CYP2C19
Uniprot ID:
P33261
Uniprot Name:
Cytochrome P450 2C19
Molecular Weight:
55930.545 Da
References
  1. He H, Tran P, Gu H, Tedesco V, Zhang J, Lin W, Gatlik E, Klein K, Heimbach T: Midostaurin, a Novel Protein Kinase Inhibitor for the Treatment of Acute Myelogenous Leukemia: Insights from Human Absorption, Metabolism, and Excretion Studies of a BDDCS II Drug. Drug Metab Dispos. 2017 May;45(5):540-555. doi: 10.1124/dmd.116.072744. Epub 2017 Mar 7. [PubMed:28270565 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
inhibitor
General Function:
Steroid hydroxylase activity
Specific Function:
Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic antidepressants.
Gene Name:
CYP2D6
Uniprot ID:
P10635
Uniprot Name:
Cytochrome P450 2D6
Molecular Weight:
55768.94 Da
References
  1. He H, Tran P, Gu H, Tedesco V, Zhang J, Lin W, Gatlik E, Klein K, Heimbach T: Midostaurin, a Novel Protein Kinase Inhibitor for the Treatment of Acute Myelogenous Leukemia: Insights from Human Absorption, Metabolism, and Excretion Studies of a BDDCS II Drug. Drug Metab Dispos. 2017 May;45(5):540-555. doi: 10.1124/dmd.116.072744. Epub 2017 Mar 7. [PubMed:28270565 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
inhibitor
General Function:
Steroid hydroxylase activity
Specific Function:
Metabolizes several precarcinogens, drugs, and solvents to reactive metabolites. Inactivates a number of drugs and xenobiotics and also bioactivates many xenobiotic substrates to their hepatotoxic or carcinogenic forms.
Gene Name:
CYP2E1
Uniprot ID:
P05181
Uniprot Name:
Cytochrome P450 2E1
Molecular Weight:
56848.42 Da
References
  1. He H, Tran P, Gu H, Tedesco V, Zhang J, Lin W, Gatlik E, Klein K, Heimbach T: Midostaurin, a Novel Protein Kinase Inhibitor for the Treatment of Acute Myelogenous Leukemia: Insights from Human Absorption, Metabolism, and Excretion Studies of a BDDCS II Drug. Drug Metab Dispos. 2017 May;45(5):540-555. doi: 10.1124/dmd.116.072744. Epub 2017 Mar 7. [PubMed:28270565 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrateinducer
General Function:
Vitamin d3 25-hydroxylase activity
Specific Function:
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4-hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiot...
Gene Name:
CYP3A4
Uniprot ID:
P08684
Uniprot Name:
Cytochrome P450 3A4
Molecular Weight:
57342.67 Da
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
inducer
General Function:
Oxygen binding
Specific Function:
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics.
Gene Name:
CYP3A5
Uniprot ID:
P20815
Uniprot Name:
Cytochrome P450 3A5
Molecular Weight:
57108.065 Da
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
inducer
General Function:
Oxygen binding
Specific Function:
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics.
Gene Name:
CYP3A7
Uniprot ID:
P24462
Uniprot Name:
Cytochrome P450 3A7
Molecular Weight:
57525.03 Da
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
inducer
General Function:
Monooxygenase activity
Specific Function:
Exhibits low testosterone 6-beta-hydroxylase activity.
Gene Name:
CYP3A43
Uniprot ID:
Q9HB55
Uniprot Name:
Cytochrome P450 3A43
Molecular Weight:
57669.21 Da
Drug created on March 19, 2008 10:39 / Updated on September 09, 2017 10:19