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Details

Stereochemistry ABSOLUTE
Molecular Formula C35H30N4O4
Molecular Weight 570.6371
Optical Activity UNSPECIFIED
Defined Stereocenters 4 / 4
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of MIDOSTAURIN

SMILES

CO[C@@H]1[C@@H](C[C@H]2O[C@]1(C)n3c4ccccc4c5c6CNC(=O)c6c7c8ccccc8n2c7c35)N(C)C(=O)C9=CC=CC=C9

InChI

InChIKey=BMGQWWVMWDBQGC-IIFHNQTCSA-N
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

HIDE SMILES / InChI
Molecular Formula C35H30N4O4
Molecular Weight 570.6371
Charge 0
Count
Stereochemistry ABSOLUTE
Additional Stereochemistry
Defined Stereocenters 4 / 4
E/Z Centers 0
Optical Activity UNSPECIFIED

Description

Midostaurin, a derivate of staurosporine (N-benzoylstaurosporine), is a broad-spectrum inhibitor of Ser/Thr and Tyr protein kinases. Midostaurin showed broad antiproliferative activity against various tumor and normal cell lines in vitro and is able to reverse the p-glycoprotein-mediated multidrug resistance of tumor cells in vitro. Midostaurin showed in vivo antitumor activity as single agent and inhibited angiogenesis in vivo. At the end of 2016 FDA granted Priority Review to the PKC412 (midostaurin) new drug application (NDA) for the treatment of acute myeloid leukemia (AML) in newly-diagnosed adults with an FMS-like tyrosine kinase-3 (FLT3) mutation, as well as for the treatment of advanced systemic mastocytosis (SM).

Originator

Approval Year

2017
82
Targets

Targets

Primary TargetPharmacologyConditionPotency
Inhibitor
7464
Myelodysplastic Syndromes
Inhibitor
7464
Myelodysplastic Syndromes
 27.0 µM [IC50]
Inhibitor
7464
Acute Myeloid Leukemia
 528.0 nM [IC50]
Conditions

Conditions

ConditionModalityTargetsHighest PhaseProduct
Primary
Receptor-type tyrosine-protein kinase FLT3
Protein kinase C alpha type
ETV6-NTRK3
Approved
7888
RYDAPT
Primary
Protein kinase C alpha type
ETV6-NTRK3
Phase III
632
Primary
Protein kinase C alpha type
ETV6-NTRK3
Phase II
1078
PubMed

PubMed

TitleDatePubMed
Analogs of staurosporine: potential anticancer drugs?
1998 Nov
Actions of the selective protein kinase C inhibitor PKC412 on B-chronic lymphocytic leukemia cells in vitro.
2002 Feb
Inhibition of mutant FLT3 receptors in leukemia cells by the small molecule tyrosine kinase inhibitor PKC412.
2002 Jun
Prostacyclin production in rat aortic smooth muscle cells: role of protein kinase C, phospholipase D and cyclooxygenase-2 expression.
2003 Nov 1
Inhibitory effect of epidermal growth factor on resveratrol-induced apoptosis in prostate cancer cells is mediated by protein kinase C-alpha.
2004 Nov
FGFR3 as a therapeutic target of the small molecule inhibitor PKC412 in hematopoietic malignancies.
2005 Dec 15
Identification of heat shock protein 32 (Hsp32) as a novel survival factor and therapeutic target in neoplastic mast cells.
2007 Jul 15
Oral small-molecule tyrosine kinase inhibitor midostaurin (PKC412) inhibits growth and induces megakaryocytic differentiation in human leukemia cells.
2009 Sep
Activation state-dependent binding of small molecule kinase inhibitors: structural insights from biochemistry.
2010 Nov 24
H1-receptor antagonists terfenadine and loratadine inhibit spontaneous growth of neoplastic mast cells.
2010 Oct
Midostaurin (PKC412) modulates differentiation and maturation of human myeloid dendritic cells.
2010 Sep
Reversible resistance induced by FLT3 inhibition: a novel resistance mechanism in mutant FLT3-expressing cells.
2011
Effects of the protein kinase inhibitor PKC412 on gene expression and link to physiological effects in zebrafish Danio rerio eleuthero-embryos.
2011 Jan
Design, synthesis, and evaluation of a novel dual FMS-like tyrosine kinase 3/stem cell factor receptor (FLT3/c-KIT) inhibitor for the treatment of acute myelogenous leukemia.
2011 Oct 27
Discovery of 3-(2,6-dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea (NVP-BGJ398), a potent and selective inhibitor of the fibroblast growth factor receptor family of receptor tyrosine kinase.
2011 Oct 27
Comprehensive analysis of kinase inhibitor selectivity.
2011 Oct 30
Comprehensive assay of kinase catalytic activity reveals features of kinase inhibitor selectivity.
2011 Oct 30
A broad activity screen in support of a chemogenomic map for kinase signalling research and drug discovery.
2013 Apr 15
Patents

Patents

20050020570
1

Sample Use Guides

In Vivo Use Guide
50 mg twice daily for 14 days
Route of Administration: Oral
In Vitro Use Guide
100 nM PKC412 treatment for 24 h induced the activation of caspase-3 and subsequently inactive the activity of PARP. Moreover, PKC412 treatment showed the inhibition of survivin, XIAP and Bcl-2 expression. The PKC412-induced apoptosis is further supported by the morphology findings that PKC412 treatment show the DNA damage and appearance of apoptotic bodies in IMS-M2 cells.
Substance Class Chemical
Created
by admin
on Mon Oct 21 20:51:48 UTC 2019
Edited
by admin
on Mon Oct 21 20:51:48 UTC 2019
Record UNII
ID912S5VON
Record Status Validated (UNII)
Record Version
  • Download
Name Type Language
MIDOSTAURIN
INN   MART.   MI   USAN   WHO-DD  
INN   USAN  
Official Name English
CGP 41251
Code English
PKC 412
Code English
RYDAPT
Brand Name English
MIDOSTAURIN [INN]
Common Name English
CGP-41251
Code English
MIDOSTAURIN [MI]
Common Name English
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
Common Name English
NVP-PKC412
Code English
PKC-412
Code English
MIDOSTAURIN [USAN]
Common Name English
MIDOSTAURIN [MART.]
Common Name English
MIDOSTAURIN [WHO-DD]
Common Name English
Classification Tree Code System Code
NCI_THESAURUS C1742
Created by admin on Mon Oct 21 20:51:48 UTC 2019 , Edited by admin on Mon Oct 21 20:51:48 UTC 2019
EU-Orphan Drug EU/3/10/765
Created by admin on Mon Oct 21 20:51:48 UTC 2019 , Edited by admin on Mon Oct 21 20:51:48 UTC 2019
FDA ORPHAN DRUG 306410
Created by admin on Mon Oct 21 20:51:48 UTC 2019 , Edited by admin on Mon Oct 21 20:51:48 UTC 2019
WHO-ATC L01XE39
Created by admin on Mon Oct 21 20:51:48 UTC 2019 , Edited by admin on Mon Oct 21 20:51:48 UTC 2019
NCI_THESAURUS C2089
Created by admin on Mon Oct 21 20:51:48 UTC 2019 , Edited by admin on Mon Oct 21 20:51:48 UTC 2019
NDF-RT N0000175605
Created by admin on Mon Oct 21 20:51:48 UTC 2019 , Edited by admin on Mon Oct 21 20:51:48 UTC 2019
FDA ORPHAN DRUG 285909
Created by admin on Mon Oct 21 20:51:48 UTC 2019 , Edited by admin on Mon Oct 21 20:51:48 UTC 2019
Code System Code Type Description
INN
7677
Created by admin on Mon Oct 21 20:51:48 UTC 2019 , Edited by admin on Mon Oct 21 20:51:48 UTC 2019
PRIMARY
ChEMBL
CHEMBL608533
Created by admin on Mon Oct 21 20:51:48 UTC 2019 , Edited by admin on Mon Oct 21 20:51:48 UTC 2019
PRIMARY
RXCUI
1919083
Created by admin on Mon Oct 21 20:51:48 UTC 2019 , Edited by admin on Mon Oct 21 20:51:48 UTC 2019
PRIMARY
NCI_THESAURUS
C1872
Created by admin on Mon Oct 21 20:51:48 UTC 2019 , Edited by admin on Mon Oct 21 20:51:48 UTC 2019
PRIMARY
PUBCHEM
9829523
Created by admin on Mon Oct 21 20:51:48 UTC 2019 , Edited by admin on Mon Oct 21 20:51:48 UTC 2019
PRIMARY
CAS
120685-11-2
Created by admin on Mon Oct 21 20:51:48 UTC 2019 , Edited by admin on Mon Oct 21 20:51:48 UTC 2019
PRIMARY
MESH
C411007
Created by admin on Mon Oct 21 20:51:48 UTC 2019 , Edited by admin on Mon Oct 21 20:51:48 UTC 2019
PRIMARY
EVMPD
SUB21040
Created by admin on Mon Oct 21 20:51:48 UTC 2019 , Edited by admin on Mon Oct 21 20:51:48 UTC 2019
PRIMARY
MERCK INDEX
M7534
Created by admin on Mon Oct 21 20:51:48 UTC 2019 , Edited by admin on Mon Oct 21 20:51:48 UTC 2019
PRIMARY Merck Index
WIKIPEDIA
Midostaurin
Created by admin on Mon Oct 21 20:51:48 UTC 2019 , Edited by admin on Mon Oct 21 20:51:48 UTC 2019
PRIMARY
Related Record Type Details
MAST/STEM CELL GROWTH FACTOR RECEPTOR KIT
TARGET -> INHIBITOR
INHIBITOR
IC50
INHIBITOR OF NUCLEAR FACTOR KAPPA-B KINASE SUBUNIT EPSILON
TARGET -> INHIBITOR
TYROSINE-PROTEIN KINASE SYK
TARGET -> INHIBITOR
INHIBITOR
IC50
RIBOSOMAL PROTEIN S6 KINASE ALPHA-1
TARGET -> INHIBITOR
TYROSINE-PROTEIN KINASE JAK1
TARGET -> INHIBITOR
RECEPTOR-TYPE TYROSINE-PROTEIN KINASE FLT3 D835Y
TARGET -> INHIBITOR
FIBROBLAST GROWTH FACTOR RECEPTOR 2
TARGET -> INHIBITOR
INHIBITOR
IC50
SERINE/THREONINE-PROTEIN KINASE N2
TARGET -> INHIBITOR
TYROSINE-PROTEIN KINASE JAK2
TARGET -> INHIBITOR
MYOSIN LIGHT CHAIN KINASE, SMOOTH MUSCLE
TARGET -> INHIBITOR
TYROSINE-PROTEIN KINASE JAK3
TARGET -> INHIBITOR
VASCULAR ENDOTHELIAL GROWTH FACTOR RECEPTOR 2
TARGET -> INHIBITOR
INHIBITOR
IC50
MATERNAL EMBRYONIC LEUCINE ZIPPER KINASE
TARGET -> INHIBITOR
PLATELET-DERIVED GROWTH FACTOR RECEPTOR BETA
TARGET -> INHIBITOR
INHIBITOR
IC50
CAMP-DEPENDENT PROTEIN KINASE CATALYTIC SUBUNIT GAMMA
TARGET -> INHIBITOR
MITOGEN-ACTIVATED PROTEIN KINASE KINASE KINASE 11
TARGET -> INHIBITOR
RECEPTOR-TYPE TYROSINE-PROTEIN KINASE FLT3
TARGET -> INHIBITOR
INHIBITOR
IC50
MACROPHAGE COLONY-STIMULATING FACTOR 1 RECEPTOR
TARGET -> INHIBITOR
INHIBITOR
IC50
PLATELET-DERIVED GROWTH FACTOR RECEPTOR ALPHA
TARGET -> INHIBITOR
INHIBITOR
IC50
PROTEIN KINASE C GAMMA TYPE
TARGET -> INHIBITOR
INHIBITOR
IC50
Related Record Type Details
Structure of CGP-62221
METABOLITE ACTIVE -> PARENT
Structure of CGP-52421
METABOLITE LESS ACTIVE -> PARENT
Related Record Type Details
Structure of MIDOSTAURIN
ACTIVE MOIETY
NIH
NCATS
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