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 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.
Accounting for 95% of recovered dose eliminated through fecal excretion, 91% was determined as metabolites and 4% as unchanged parent drug. Remaining 5% of the recovered dose is eliminated via renal excretion.
The Vd of midostaurin is 95.2L. The parent drug and its main metabolites (CGP62221, CGP52421) are distributed in plasma in vitro.
The clearance values of during the initial formation of metabolites are 1.47 L/h for CGP62221 metabolite and 0.501 L/h for CGP52421. 28 days following the oral administration of midostaurin, the clearance of CGP52421 may increase up to 5.2 fold in a recommended dose of 25 mg, resulting in a 2.1- to 2.5-fold increase in total clearance of midostaurin.

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Metabolism / Metabolites
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.

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Biological Half-Life
Elimination half life is approximately 21 hrs for midostaurin, 32 hrs for CGP62221 and 482 hrs for CGP52421.

Hepatotoxicity
Elevations in serum aminotransferase levels are common during midostaurin therapy occurring in up to 71% of patients with AML also receiving standard induction therapy and rising above 5 times the upper limit of the normal range in 20%. In patients with systemic mastocytosis receiving midostaurin monotherapy, ALT elevations arose in 31% of patients and rose to above 5 times ULN in 4%. Hyperbilirubinemia was also common in these studies but instances of clinically apparent liver injury with jaundice, severe hepatoxicity and deaths from hepatic failure were not reported. However, because of the limited clinical experience with the use of midostaurin and other FLT3 inhibitors, their potential for causing liver injury is not well defined.
Likelihood score: E* (unproven but suspected cause of clinically apparent liver injury).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
No information is available on the clinical use of midostaurin during breastfeeding. Because midostaurin and its active metabolites are 99.8% bound to plasma proteins, the amount in milk is likely to be low. The manufacturer recommends that breastfeeding be discontinued during midostaurin therapy and for 4 months after the last dose. Avoiding breastfeeding is particularly important when midostaurin is given with other cancer chemotherapy agents.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Protein Binding
Midostaurin predominantly binds to α1-acid glycoprotein in vitro. The parent drug and its metabolites are >99.8% bound to plasma proteins in vitro.

[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.

Midostaurin is an organic heterooctacyclic compound that is the N-benzoyl derivative of staurosporine. It has a role as an EC 2.7.11.13 (protein kinase C) inhibitor and an antineoplastic agent. It is an indolocarbazole, an organic heterooctacyclic compound, a member of benzamides and a gamma-lactam. It is functionally related to a staurosporine.
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.
Midostaurin is a Kinase Inhibitor. The mechanism of action of midostaurin is as a Receptor Tyrosine Kinase Inhibitor.
Midostaurin is an orally available small molecule inhibitor of FMS-like tyrosine kinase 3 (FLT3) which is used as an antineoplastic agent in the treatment of acute myeloid leukemia with FLT3 mutations. Midostaurin is associated with a moderate rate of serum aminotransferase elevations during therapy and is suspected to cause rare instances of clinically apparent acute liver injury.
Midostaurin is a synthetic indolocarbazole multikinase inhibitor with potential antiangiogenic and antineoplastic activities. Midostaurin inhibits protein kinase C alpha (PKCalpha), vascular endothelial growth factor receptor 2 (VEGFR2), c-kit, platelet-derived growth factor receptor (PDGFR) and FMS-like tyrosine kinase 3 (FLT3) tyrosine kinases, which may result in disruption of the cell cycle, inhibition of proliferation, apoptosis, and inhibition of angiogenesis in susceptible tumors.

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Drug Indication
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).
FDA Label
Rydapt is indicated: in combination with standard daunorubicin and cytarabine induction and high dose cytarabine consolidation chemotherapy, and for patients in complete response followed by Rydapt single agent maintenance therapy, for adult patients with newly diagnosed acute myeloid leukaemia (AML) who are FLT3 mutation positive (see section 4. 2); as monotherapy for the treatment of adult patients with aggressive systemic mastocytosis (ASM), systemic mastocytosis with associated haematological neoplasm (SM AHN), or mast cell leukaemia (MCL).
Treatment of acute myeloid leukaemia, Treatment of malignant mastocytosis, Treatment of mast cell leukaemia

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Mechanism of Action
It potently inhibits multiple receptor tyrosine kinases. Midostaurin and its major active metabolites CGP62221 and CGP52421 inhibit the activity of protein kinase C alpha (PKCalpha), VEGFR2, KIT, PDGFR and WT and/or mutant FLT3 tyrosine kinases. Inhibition of FLT3 receptor signalling cascades induces apoptosis of target leukemia cells expressing target receptors and mast cells, in addition to its antiproliferative activity toward multiple cancer cell lines. Midostaurin also interacts with organic anion transporter (OATP) 1A1 and multidrug resistance protein (MRP)-2 according to preliminary in vitro studies.

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Pharmacodynamics
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.

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.)