nPKC-η (IC50 = 16 nM); cPKC-α (IC50 = 22 nM); cPKC-γ (IC50 = 24 nM); cPKC-β1 (IC50 = 30 nM); cPKC-β2 (IC50 = 31 nM); nPKC-δ (IC50 = 33 nM); PPK (IC50 = 38 nM); KDR (IC50 = 86 nM); c-Syk (IC50 = 95 nM); cdk1/cycB (IC50 = 570 nM); Protein kinase A (IC50 = 570 nM); c-Fgr (IC50 = 790 nM); c-Src (IC50 = 800 nM); Flt-1 (IC50 = 912 nM); EGF-R (IC50 = 1100 nM); nPKC-ε (IC50 = 1250 nM); aPKC-ζ (IC50 = 465000 nM); Myosin-light chain kinase (IC50 = 1900 nM); Flk-1 (IC50 = 3900 nM); c-Lyn (IC50 = 4300 nM); P70S6 kinase (IC50 = 5000 nM); CSK (IC50 = 8000 nM)

Midostaurin (PKC412) reverses Pgp-mediated multidrug effects on cellular malignancies in vitro and has wide antiproliferative efficacy against a variety of tumor and normal cell lines. Cell cycle is induced when cells are exposed to midostaurin (PKC412). Midostaurin (PKC412) strongly inhibits KIT-, Lyn-, and STAT5 activities, but not HMC-1. In hematopoietic Ba/F3 cells, midostaurin (PKC412) inhibits EN fusion tyrosine kinase. EN phosphorylation in M0-91 and IMS-M2 cells is strongly inhibited by midostaurin (PKC412) in a dose-dependent manner [4].

Both laser-induced choroidal neovascularization and neovascularization in angiogenesis models are significantly inhibited by midostaurin (PKC412) [1]. In mice with tumor overexpression, midostaurin (PKC412) (25 mg/kg, i.p.) shields the K18 Arg90Cys murine scaffold Fas-sensing cellular adapter [5].

Absorption, Distribution and Excretion
The time to reach maximum concentration in fasting patients is 1–3 hours. After a standard meal, the maximum concentration and its time to reach can be shortened by up to 20%. 95% of the recovered dose is excreted in feces, of which 91% is metabolites and 4% is the parent drug. The remaining 5% of the recovered dose is excreted by the kidneys. The volume of distribution (Vd) of midotulin is 95.2 L. Distribution of the parent drug and its major metabolites (CGP62221, CGP52421) in in vitro plasma is shown. The initial clearance rates of the metabolites are: 1.47 L/h for CGP62221 metabolites and 0.501 L/h for CGP52421 metabolites. After 28 days of oral administration of midostaurin at the recommended dose of 25 mg, the clearance of CGP52421 increased by up to 5.2-fold, resulting in a 2.1- to 2.5-fold increase in the total clearance of midostaurin. Metabolites/Metabolites Midostaurin is primarily metabolized by hepatic CYP3A4 enzyme activity to CGP62221 and CGP52421. The metabolism of CGP62221 is initially linear, while the formation of CGP52421 is an induced process. Biological Half-Life The elimination half-life of midostaurin is approximately 21 hours, that of CGP62221 is approximately 32 hours, and that of CGP52421 is approximately 482 hours.

Hepatotoxicity
Elevated serum transaminase levels are common during midostaurin treatment, occurring in up to 71% of patients with acute myeloid leukemia (AML) receiving standard induction therapy, with 20% of these patients having transaminase levels exceeding 5 times the upper limit of normal. In patients with systemic mastocytic leukemia receiving midostaurin monotherapy, elevated alanine aminotransferase (ALT) levels were observed in 31% of patients, with 4% having ALT levels exceeding 5 times the upper limit of normal. Hyperbilirubinemia was also common in these studies, but no cases of clinically significant liver injury (e.g., jaundice), severe hepatotoxicity, or death due to liver failure were reported. However, due to limited clinical experience with midostaurin and other FLT3 inhibitors, the likelihood of liver injury is unclear. Probability Score: E (Unproven but suspected cause of clinically significant liver injury). Pregnancy and Lactation Effects ◉ Overview of Use During Lactation There is currently no information on the clinical use of midostaurin during lactation. Because midostaurin and its active metabolites bind to plasma proteins at a rate as high as 99.8%, their concentration in breast milk may be very low. The manufacturer recommends discontinuing breastfeeding during midostaurin treatment and for four months after the last dose. Avoiding breastfeeding is especially important when midostaurin is used in combination with other anticancer chemotherapy drugs.
◉ Effects on breastfed infants
No published information found as of the revision date.
◉ Effects on lactation and breast milk
No published information found as of the revision date.

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Protein binding
Midostaurin binds primarily to α1-acid glycoprotein in vitro. The binding rate of the active drug and its metabolites to plasma proteins in vitro is >99.8%.

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

[2]. 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.

[3]. Midostaurin upregulates eNOS gene expression and preserves eNOS function in the microcirculation of the mouse. Nitric Oxide. 2005 Jun;12(4):231-6.

[4]. Synergistic growth-inhibitory effects of Midostaurin (PKC412) on neoplastic mast cells carrying KIT D816V. Haematologica. 2013 Sep;98(9):1450-7.

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

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

Midotulin is an organic heterocyclic octane compound, an N-benzoyl derivative of asteroidin. It is an EC 2.7.11.13 (protein kinase C) inhibitor and an antitumor drug. It is an indolecarbazole compound, belonging to the organic heterocyclic octane compound class, and is a benzamide and γ-lactam compound. Its function is similar to asteroidin. Midotulin (trade name: Redap) is a multi-target kinase inhibitor used to treat newly diagnosed acute myeloid leukemia (AML) in adults with specific FLT3 gene mutations. Initially, it was considered a potential broad-spectrum antitumor drug, effective against various solid tumors and hematopoietic system tumors. The drug was approved for marketing on April 28, 2017, and has been shown to be effective as adjuvant therapy in combination with chemotherapy drugs, improving overall survival in patients with acute myeloid leukemia (AML). Midotulin is a kinase inhibitor. Its mechanism of action is as a receptor tyrosine kinase inhibitor. Midotulin is an oral, small-molecule FMS-like tyrosine kinase 3 (FLT3) inhibitor, an anti-tumor drug used to treat FLT3-mutant acute myeloid leukemia. Elevated serum transaminases are moderately common during midotulin treatment, and rare, clinically significant acute liver injury is suspected. Midotulin is a synthetic indolecarbazole multi-kinase inhibitor with potential anti-angiogenic and anti-tumor activities. It inhibits protein kinase Cα (PKCα), vascular endothelial growth factor receptor 2 (VEGFR2), c-kit, platelet-derived growth factor receptor (PDGFR), and FMS-like tyrosine kinase 3 (FLT3), potentially leading to cell cycle disruption, proliferation inhibition, apoptosis, and inhibition of angiogenesis in susceptible tumors.

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Drug Indications
Studied for the treatment of adult patients with high-risk FLT3 mutation-positive acute myeloid leukemia (AML), aggressive systemic mastocytic hyperplasia (ASM), systemic mastocytic hyperplasia with hematologic malignancies (SM-AHN), or mast cell leukemia (MCL).
FDA Label
Rydapt Indications: Rydapt is indicated for the treatment of newly diagnosed adult patients with FLT3 mutation-positive acute myeloid leukemia (AML) in combination with standard daunorubicin and cytarabine induction regimens, as well as for consolidation chemotherapy with high-dose cytarabine in combination with daunorubicin, and for maintenance therapy as monotherapy in patients with complete remission (see Section 4.2); and as monotherapy for the treatment of adult patients with aggressive systemic mastocytic hyperplasia (ASM), systemic mastocytic hyperplasia with hematologic malignancies (SM-AHN), or mast cell leukemia (MCL).
Treatment of acute myeloid leukemia, treatment of malignant mast cell hyperplasia, treatment of mast cell leukemia
Mechanism of Action
It can potently inhibit multiple receptor tyrosine kinases. Midostaurin and its main active metabolites CGP62221 and CGP52421 can inhibit the activity of protein kinase Cα (PKCα), VEGFR2, KIT, PDGFR, and wild-type and/or mutant FLT3 tyrosine kinase. Inhibition of the FLT3 receptor signaling cascade can induce apoptosis in targeted leukemia cells and mast cells expressing the target receptor. In addition, it also has anti-proliferative activity against various cancer cell lines. Preliminary in vitro studies have shown that midostaurin can also interact with organic anion transporter (OATP) 1A1 and multidrug resistance protein (MRP)-2. Pharmacodynamics It targets multiple wild-type and mutant kinases. Once activated, these kinases continuously stimulate abnormal signaling cascades, leading to the development of malignancies such as acute myeloid leukemia (AML) and acute leiomyomatosis (ASM). Compared to placebo, the pharmacodynamic effect of midostaurin in prolonging the QTc interval was not clinically significant in patients with advanced systemic mastocytosis (SM) or acute myeloid leukemia (AML). Midostaurin provides therapeutic benefit as a combination therapy with chemotherapy for patients receiving chemotherapy.

C35H30N4O4

570.64

570.226

120685-11-2

Midostaurin-d5

9829523

White to yellow solid powder

1.5±0.1 g/cm3

235-260

1.770

5.27

1

4

3

43

1140

4

C[C@@]12[C@@H]([C@@H](C[C@@H](O1)N3C4=CC=CC=C4C5=C6C(=C7C8=CC=CC=C8N2C7=C53)CNC6=O)N(C)C(=O)C9=CC=CC=C9)OC

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

N-[(2S,3R,4R,6R)-3-methoxy-2-methyl-16-oxo-29-oxa-1,7,17-triazaoctacyclo[12.12.2.12,6.07,28.08,13.015,19.020,27.021,26]nonacosa-8,10,12,14,19,21,23,25,27-nonaen-4-yl]-N-methylbenzamide hydrochloride

Midostaurin; 120685-11-2; PKC412; Cgp 41251; 4'-N-Benzoylstaurosporine; PKC-412; Benzoylstaurosporine; RYDAPT;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~50 mg/mL (~87.62 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (4.38 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (4.38 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)