MIDOSTAURIN

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 Search

SMILES

[H][C@]12C[C@H]([C@@H](OC)[C@](C)(O1)N3C4=CC=CC=C4C5=C6CNC(=O)C6=C7C8=C(C=CC=C8)N2C7=C35)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

Description
Sources: https://www.ncbi.nlm.nih.gov/pubmed/10454207
Curator's Comment: description was created based on several sources, including: https://www.novartis.com/news/media-releases/novartis-drug-pkc412-midostaurin-granted-fda-priority-review-newly-diagnosed | http://adisinsight.springer.com/drugs/800002524

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

Targets

Primary Target	Pharmacology	Potency
Receptor-type tyrosine-protein kinase FLT3 4 Target ID: CHEMBL2034796 Sources: https://www.ncbi.nlm.nih.gov/pubmed/12124173	Inhibitor 8297	528.0 nM [IC50]
ETV6-NTRK3 1 Target ID: ETV6-NTRK3 Sources: https://www.ncbi.nlm.nih.gov/pubmed/23131561	Inhibitor 8297
Protein kinase C alpha type 5 Target ID: P04409 Gene ID: 282001.0 Gene Symbol: PRKCA Target Organism: Bos taurus (Bovine) Sources: https://www.ncbi.nlm.nih.gov/pubmed/10454207	Inhibitor 8297	27.0 µM [IC50]

Conditions

Condition	Modality	Highest Phase	Product
Acute myeloid leukemia 136 Sources: http://adisinsight.springer.com/drugs/800002524 https://www.drugs.com/history/rydapt.html	Primary	Approved 8429	RYDAPT Approved Use RYDAPT is a kinase inhibitor indicated for the treatment of adult patients with: Newly diagnosed acute myeloid leukemia (AML) that is FLT3 mutation-positive as detected by an FDA-approved test, in combination with standard cytarabine and daunorubicin induction and cytarabine consolidation Launch Date 2017
Myelodysplastic syndromes 58 Sources: https://www.ncbi.nlm.nih.gov/pubmed/25530214 https://www.ncbi.nlm.nih.gov/pubmed/20733134	Primary	Phase III 656	Unknown Approved Use Unknown
Aggressive systemic mastocytosis 2 Sources: https://www.ncbi.nlm.nih.gov/pubmed/27355555	Primary	Phase II 1132	Unknown Approved Use Unknown

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:63452	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:63452
ChemicalBook	CB71315281	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB71315281
MolPort	MolPort-023-276-626	https://www.molport.com/shop/molecule-link/MolPort-023-276-626
Selleck Chemicals	midostaurin-pkc412	http://www.selleckchem.com/products/midostaurin-pkc412.html
ZINC	ZINC000100013130	http://zinc15.docking.org/substances/ZINC000100013130
eMolecules	27315532	https://www.emolecules.com/cgi-bin/more?vid=27315532

PubMed

Title	Date	PubMed
Analogs of staurosporine: potential anticancer drugs?	1998 Nov	9809468
Inhibition of mutant FLT3 receptors in leukemia cells by the small molecule tyrosine kinase inhibitor PKC412.	2002 Jun	12124173
Inhibitory effect of epidermal growth factor on resveratrol-induced apoptosis in prostate cancer cells is mediated by protein kinase C-alpha.	2004 Nov	15542774
Activation state-dependent binding of small molecule kinase inhibitors: structural insights from biochemistry.	2010 Nov 24	21095574
Midostaurin (PKC412) modulates differentiation and maturation of human myeloid dendritic cells.	2010 Sep	20685248
Reversible resistance induced by FLT3 inhibition: a novel resistance mechanism in mutant FLT3-expressing cells.	2011	21980431
Effects of the protein kinase inhibitor PKC412 on gene expression and link to physiological effects in zebrafish Danio rerio eleuthero-embryos.	2011 Jan	20980353
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	21936542
Comprehensive analysis of kinase inhibitor selectivity.	2011 Oct 30	22037378

Patents

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.

Name

Type

Language

MIDOSTAURIN

Official Name

English

MIDOSTAURIN [ORANGE BOOK]

Common Name

English

CGP 41251

Code

English

PKC 412

Code

English

NSC-656576

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

Midostaurin [WHO-DD]

Common Name

English

MIDOSTAURIN [JAN]

Common Name

English

PKC-412

Code

English

MIDOSTAURIN [USAN]

Common Name

English

MIDOSTAURIN [MART.]

Common Name

English

Classification Tree Code System Code

NCI_THESAURUS

C1742