Midostaurin
Synonym(s):PKG Inhibitor IX, N-Benzoylstaurosporine, CGP 41 251, PDGFR Tyrosine Kinase Inhibitor X, PKC412;PKG Inhibitor IX, N-Benzoylstaurosporine, CGP 41 251, PKC412, PDGFR Tyrosine Kinase Inhibitor X;Staurosporine, N-Benzoyl
- CAS NO.:120685-11-2
- Empirical Formula: C35H30N4O4
- Molecular Weight: 570.64
- MDL number: MFCD10687105
- EINECS: 999-999-2
- SAFETY DATA SHEET (SDS)
- Update Date: 2024-11-19 15:53:33
What is Midostaurin?
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.
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 . Incidences of pulmonary toxicities including interstitial lung disease and pneumonitis have occured in few patients undergoing midostaurin monotherapy or combination therapy.
Description
PKC-412 (120685-11-2) is a broad spectrum kinase inhibitor. Inhibited kinases include, but are not limited to; PKA, PKC, S6 Kinase, KDR, PKC, Akt, EGFR, VEGFR, PDGFR, c-kit, and FLT-3. Acute myeloid leukemia related mutant forms of FLT-3 are also inhibited both in vitro and in vivo. PKC-412 has been demonstrated to induce apoptosis and shows broad antiproliferative activity in various tumor cell lines. Cell Permeable
The Uses of Midostaurin
Midostaurin was shown to possess antiproliferative characteristics via inhibition of protein kinase C, kinase insert domain receptor, and c-kit.
The Uses of Midostaurin
Midostaurin is used as a broad spectrum protein kinase inhibitor. Inhibits conventional PKC isoforms (α, β, γ), PDFRβ, VEGFR2, Syk, PKCη, Flk-1, Flt3, Cdk1/B, PKA, c-Kit, c-Fgr, c-Src, VEGFR1 and EGFR. Displays potent antitumor activity. Due to this act which may result in disruption of the cell cycle, inhibition of proliferation, apoptosis, and inhibition of angiogenesis in susceptible tumors. Midostaurin was shown to possess antiproliferative characteristics via inhibition of protein kinase C, kinase insert domain receptor, and c-kit.
Indications
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).
Background
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 . 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.
What are the applications of Application
PKC-412 is a broad spectrum tyrosine kinase inhibitor
Definition
ChEBI: An organic heterooctacyclic compound that is the N-benzoyl derivative of staurosporine.
brand name
Rydapt
General Description
Class: receptor tyrosine kinase; Treatment: AML, SM; Other name: PKC-412, CGP41251; Elimination half-life = 20 h; Protein binding > 99%
Biological Activity
Broad spectrum protein kinase inhibitor. Inhibits conventional PKC isoforms ( α , β , γ ), PDFR β , VEGFR2, Syk, PKCη, Flk-1, Flt3, Cdk1/B, PKA, c-Kit, c-Fgr, c-Src, VEGFR1 and EGFR. Displays potent antitumor activity.
Pharmacokinetics
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.
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 .
storage
Store at -20°C
References
1) Odgerel et al. (2008) The FLT3 inhibitor PKC412 exerts differential cell cycle effects on leukemic cells depending on the presence of FLT3 mutations; Oncogene, 27 3102 2) El Fitori et al. (2007) PKC 412 small-molecule tyrosine kinase inhibitor: single-compound therapy for pancreatic cancer; Cancer, 110 1457 3) Miyatake, et al. ( 2007) PKC412 (CGP41251) modulates the proliferation and lipopolysaccharide-induced inflammatory responses of RAW 264.macrophages; Biochem. Biophys. Res. Commun., 360 115 4) Bahlis et.al. (2005) N-Benzoylstaurosporine (PKC412) inhibits Akt kinase inducing apoptosis in multiple myeloma cells; Leuk. Lymphoma, 46 899 5) Fabbro et al., (2000) PKC-412 – a protein kinase inhibitor with a broad therapeutic potential; Anticancer Drug Des., 15 17
Properties of Midostaurin
Melting point: | 235-260℃ |
Density | 1.47±0.1 g/cm3(Predicted) |
storage temp. | Sealed in dry,Store in freezer, under -20°C |
solubility | Soluble in DMSO (15 mg/ml), MDC (10 mg/ml), methanol (5 mg/ml), 100% ethanol (2.5 mg/ml), and DMF (20 mg/ml). |
form | Tan solid |
pka | 14.19±0.70(Predicted) |
color | White |
Stability: | Stable for 2 years from date of purchase as supplied. Solutions in DMSO or ethanol may be stored at -20°C for up to 2 months. |
Safety information for Midostaurin
Signal word | Danger |
Pictogram(s) |
Health Hazard GHS08 |
Precautionary Statement Codes |
P201:Obtain special instructions before use. P202:Do not handle until all safety precautions have been read and understood. P280:Wear protective gloves/protective clothing/eye protection/face protection. P308+P313:IF exposed or concerned: Get medical advice/attention. P405:Store locked up. P501:Dispose of contents/container to..… |
Computed Descriptors for Midostaurin
Abamectin manufacturer
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