Midostaurin

Names

[ CAS No. ]:
120685-11-2

[ Name ]:
Midostaurin

[Synonym ]:
4'-N-benzoylstaurosporine
Benzamide, N-[(6S,7R,8R,10R)-7,8,9,10,17,18-hexahydro-7-methoxy-6-methyl-16-oxo-6,10-epoxy-6H,16H-diindolo[1,2,3-gh:3',2',1'-lm]pyrrolo[3,4-j][1,7]benzodiazonin-8-yl]-N-methyl-
PKC 412,[9S-(9α,10β,11β,13α)]-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
Cgp 41 251
Midostaurin
4'-N-benzoyl staurosprine
Benzoylstaurosporine
N-[(2S,3R,4R,6R)-3-Methoxy-2-methyl-16-oxo-29-oxa-1,7,17-triazaoctacyclo[12.12.2.1.0.0.0.0.0]nonacosa-8,10,12,14,19,21,23,25,27-nonaen-4-yl]-N-methylbenzamide
PKC412
PKC-412

Biological Activity

[Description]:

Midostaurin (CGP41231; PKC412) is a multi-targeted protein kinase inhibitor which inhibits PKCα/β/γ, Syk, Flk-1, Akt, PKA, c-Kit, c-Fgr, c-Src, FLT3, PDFRβ and VEGFR1/2 with IC50 ranging from 16-500 nM.

[Related Catalog]:

Signaling Pathways >> Epigenetics >> PKC

Signaling Pathways >> TGF-beta/Smad >> PKC

Research Areas >> Cancer

[Target]

nPKC-η:16 nM (IC50)

cPKC-α:22 nM (IC50)

cPKC-γ:24 nM (IC50)

cPKC-β1:30 nM (IC50)

cPKC-β2:31 nM (IC50)

nPKC-δ:33 nM (IC50)

nPKC-ε:1250 nM (IC50)

aPKC-ζ:465000 nM (IC50)

PPK:38 nM (IC50)

KDR:86 nM (IC50)

c-Syk:95 nM (IC50)

cdk1/cycB:570 nM (IC50)

Protein kinase A:570 nM (IC50)

c-Fgr:790 nM (IC50)

c-Src:800 nM (IC50)

Flt-1:912 nM (IC50)

EGF-R:1100 nM (IC50)

Myosin-light chain kinase:1900 nM (IC50)

Flk-1:3900 nM (IC50)

c-Lyn:4300 nM (IC50)

P70S6 kinase:5000 nM (IC50)

CSK:8000 nM (IC50)

[In Vitro]

Midostaurin (PKC412) shows a broad antiproliferative activity against various tumor and normal cell lines in vitro, and is able to reverse the Pgp-mediated multidrug resistance of tumor cells in vitro. Exposure of cells to Midostaurin (PKC412) results in a dose-dependent increase in the G2/M phase of the cell cycle concomitant with increased polyploidy, apoptosis and enhanced sensitivity to ionizing radiation[1]. Midostaurin (PKC412) with ponatinib induced substantial inhibition of KIT-, Lyn-, and STAT5 activity, but did not suppress Btk in HMC-1 cells and primary neoplastic mast cells[2]. Midostaurin (PKC412) inhibits EN fusion tyrosine kinase in hematopoietic Ba/F3 cells. Midostaurin (PKC412) significantly inhibits EN phosphorylation in M0-91 and IMS-M2 cells in a dose-dependent manner[3].

[In Vivo]

Midostaurin (PKC412) strongly inhibits retinal neovascularization as well as laser-induced choroidal neovascularization in murine models[1]. Midostaurin (PKC412) (25 mg/kg, i.p.) protects mouse livers of the K18 Arg90Cys-overexpressing transgenic mice from Fas-induced apoptosis[4].

[Cell Assay]

Proliferation is determined by trypan blue dye exclusion test. Cells in suspension are seeded in six-well plates at a density of 1×105 cells/mL in the presence of different concentrations of PKC412 for 3 days. In control wells, DMSO instead of Midostaurin (PKC412) is added. After the treatment, 10 μL of the cell suspension is mixed with 10 μL of 0.4% trypan blue, and alive cells are counted manually using a hemacytometer. Results are calculated as the percentage of the values measured when cells are grown in the absence of the reagent. All experiments are performed in triplicate[3].

[Animal admin]

K8-deficient, K18-deficient, and human K18 R90C-overexpressing mice with age of 6-8 weeks are used in the assay. Age and sex matched mice are treated with Midostaurin (25 mg/kg), daily for 4 d or with an equal volume of DMSO as vehicle (both administered intraperitoneally). On day 5 post-treatment, apoptosis is induced by intraperitoneal injection of Fas ligand (Fas-L) (0.15 μg/g body weight). Mice are fasted overnight before Fas Ab injection, and 18 mice are used per DMSO or Midostaurin (PKC412) group for the Fas-treated mice while 6 mice are used per DMSO or Midostaurin (PKC412) group for the control non-Fas-treated mice. Mice are sacrificed by CO2 inhalation 6 h after Fas Ab injection. Blood is collected by intracardiac puncture, and livers are harvested for hematoxylin and eosin (HE) staining (after fixation in 10% formalin) or frozen in optimum cutting temperature compound for immunofluorescence staining[4].

[References]

[1]. Fabbro D, et al. PKC412--a protein kinase inhibitor with a broad therapeutic potential. Anticancer Drug Des. 2000 Feb;15(1):17-28.

[2]. Gleixner KV, et al. Synergistic growth-inhibitory effects of ponatinib and midostaurin (PKC412) on neoplastic mast cells carrying KIT D816V. Haematologica. 2013 Sep;98(9):1450-7.

[3]. Chi HT, et al. ETV6-NTRK3 as a therapeutic target of small molecule inhibitor PKC412. Biochem Biophys Res Commun. 2012 Dec 7;429(1-2):87-92.

[4]. Kwan R, et al. PKC412 normalizes mutation-related keratin filament disruption and hepatic injury in mice by promoting keratin-myosin binding. Hepatology. 2015 Dec;62(6):1858-69.

[5]. Fabbro D, et al. Inhibitors of protein kinases: CGP 41251, a protein kinase inhibitor with potential as an anticancer agent. Pharmacol Ther. 1999 May-Jun;82(2-3):293-301.

[Related Small Molecules]

Chemical & Physical Properties

[ Density]:
1.5±0.1 g/cm3

[ Molecular Formula ]:
C₃₅H₃₀N₄O₄

[ Molecular Weight ]:
570.637

[ Exact Mass ]:
570.226685

[ PSA ]:
77.73000

[ LogP ]:
5.27

[ Index of Refraction ]:
1.770

[ Storage condition ]:
-20℃

Safety Information

[ Hazard Codes ]:
T: Toxic;

Related Compounds

The content on this webpage is sourced from various professional data sources. If you have any questions or concerns regarding the content, please feel free to contact service1@chemsrc.com.