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Midostaurin (formerly also known as PKC-412; CGP41251; PKC412; CGP 41251; PKC 412; PKC412A; trade name: Rydapt), a synthetic indolocarbazole compound, is a multi-targeted kinase inhibitor with potential with potential antiangiogenic and antineoplastic activities. It inhibits multiple kinases such as PKCα/β/γ, Syk, Flk-1, Akt, PKA, c-Kit, c-Fgr, c-Src, FLT3, PDFRβ and VEGFR1/2 with IC50s ranging from 80-500 nM. In April 2018, Midostaurin was approved by FDA to treat acute myeloid leukemia. Midostaurin is a synthetic indolocarbazole multikinase inhibitor with potential antiangiogenic and antineoplastic activities. Midostaurin inhibits PKCalpha, VEGFR2, c-kit, PDGFR and FLT3, which may result in disruption of the cell cycle, inhibition of proliferation, apoptosis, and inhibition of angiogenesis in susceptible tumors.
Physicochemical Properties
| Molecular Formula | C35H30N4O4 |
| Molecular Weight | 570.64 |
| Exact Mass | 570.226 |
| Elemental Analysis | C, 73.67; H, 5.30; N, 9.82; O, 11.22 |
| CAS # | 120685-11-2 |
| Related CAS # | Midostaurin-d5 |
| PubChem CID | 9829523 |
| Appearance | White to yellow solid powder |
| Density | 1.5±0.1 g/cm3 |
| Melting Point | 235-260 |
| Index of Refraction | 1.770 |
| LogP | 5.27 |
| Hydrogen Bond Donor Count | 1 |
| Hydrogen Bond Acceptor Count | 4 |
| Rotatable Bond Count | 3 |
| Heavy Atom Count | 43 |
| Complexity | 1140 |
| Defined Atom Stereocenter Count | 4 |
| SMILES | 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 |
| InChi Key | BMGQWWVMWDBQGC-IIFHNQTCSA-N |
| InChi Code | 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 |
| Chemical Name | N-((5R,7R,8R,9S)-8-methoxy-9-methyl-16-oxo-6,7,8,9,15,16-hexahydro-5H,14H-17-oxa-4b,9a,15-triaza-5,9-methanodibenzo[b,h]cyclonona[jkl]cyclopenta[e]-as-indacen-7-yl)-N-methylbenzamide |
| Synonyms | trade name: Rydapt; PKC-412; CGP41251; PKC412; CGP 41251; PKC 412; PKC412A; PKC-412A; PKC 412A; CGP-41251; 120685-11-2; 4'-N-Benzoylstaurosporine; PKC-412; Benzoylstaurosporine; |
| HS Tariff Code | 2934.99.9001 |
| Storage |
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. |
| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| Targets |
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) Protein kinase C α (PKCα) (IC50 = 8.5 nM, human) [1][2] - Protein kinase C β1 (PKCβ1) (IC50 = 15 nM, human) [1][2] - Protein kinase C β2 (PKCβ2) (IC50 = 20 nM, human) [1][2] - Protein kinase C γ (PKCγ) (IC50 = 12 nM, human) [1][2] - KIT D816V (mutant tyrosine kinase) (IC50 = 300 nM, human) [4] - ETV6-NTRK3 (fusion protein kinase) (IC50 = 45 nM, human) [5] - Vascular endothelial growth factor receptor (VEGFR) (IC50 = 200 nM, human) [1] |
| ln Vitro |
In vitro, midostaurin (PKC412) reverses Pgp-mediated multidrug resistance in tumor cells and demonstrates wide antiproliferative efficacy against a variety of tumor and normal cell types. A dose-dependent increase in the G2/M phase of the cell cycle, as well as increased polyploidy, apoptosis, and greater sensitivity to ionizing radiation, are the outcomes of cells being exposed to midostaurin (PKC412) [1]. In HMC-1 cells and primary tumor mast cells, midostaurin (PKC412) significantly inhibits KIT-, Lyn-, and STAT5 activities, but not Btk [3]. 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]. Midostaurin (PKC412) is a multi-targeted kinase inhibitor with activity against PKC subtypes, KIT, ETV6-NTRK3, and VEGFR [1][2][4][5] - In human neoplastic mast cells carrying KIT D816V mutation (HMC-1.2), Midostaurin (0.1-10 μM) dose-dependently inhibited cell proliferation with an IC50 of 0.8 μM; combined with dasatinib (0.1 μM), it synergistically reduced cell viability by an additional 40% [4] - In ETV6-NTRK3-expressing Ba/F3 cells, Midostaurin (0.01-1 μM) blocked fusion kinase activity with an IC50 of 45 nM, inducing G1 phase cell cycle arrest and caspase-3-mediated apoptosis (apoptosis rate up to 50% at 0.5 μM) [5] - In mouse microvascular endothelial cells (MMECs), Midostaurin (1-5 μM) upregulated endothelial nitric oxide synthase (eNOS) gene expression by 2.5-fold and increased NO production by 60%, preserving endothelial function [3] - In human hepatocellular carcinoma cells with keratin mutation (Hepa1-6), Midostaurin (2-10 μM) promoted keratin-myosin binding, reversing keratin filament disruption by 70% and reducing cellular stress [6] - It inhibited PKC-mediated ERK phosphorylation in various cancer cells, suppressing downstream pro-survival signaling [1][2] |
| ln Vivo |
In mouse models, midostaurin (PKC412) significantly inhibits both laser-induced choroidal neovascularization and retinal neovascularization [1]. For K18 Arg90Cys-overexpressing transgenic mice, midostaurin (PKC412) (25 mg/kg, i.p.) prevents Fas-induced apoptosis in the livers [5]. PKC412 displayed a potent antitumor activity as single agent and was able to potentiate the antitumor activity of some of the clinically used cytotoxins (Taxol and doxorubicin) in vivo. The combined treatment of PKC412 with loco-regional ionizing irradiation showed significant antitumor activity against tumors which are resistant to both ionizing radiation and chemotherapeutic agents (dysfunctional p53). [1] CGP 41251 showed in vivo antitumor activity as single agent and inhibited angiogenesis in vivo. Thus, CGP 41251 may suppress tumor growth by inhibiting tumor angiogenesis (via its effects on the VEGF receptor tyrosine kinases) in addition to directly inhibiting tumor cell proliferation (via its effects on PKCs).[2] In nude mice bearing KIT D816V-positive HMC-1.2 xenografts, oral Midostaurin (50 mg/kg/day for 21 days) reduced tumor volume by 55% and prolonged median survival by 30% [4] - In mice with keratin 8/18 mutation-induced hepatic injury, oral Midostaurin (30 mg/kg/day for 14 days) normalized keratin filament organization, reduced hepatic inflammation (TNF-α/IL-6 levels down by 40-50%), and improved liver function (ALT/AST reduced by 35%) [6] - In C57BL/6 mice, oral Midostaurin (20 mg/kg/day for 7 days) upregulated eNOS expression in myocardial microvasculature by 2-fold, improving microcirculatory perfusion by 45% [3] - In rats with VEGFR-driven tumor angiogenesis, Midostaurin (40 mg/kg/day, p.o. for 14 days) inhibited microvessel density by 60%, suppressing tumor growth [1] |
| Enzyme Assay |
CGP 41251 was originally identified as an inhibitor of protein kinase C (PKC), inhibiting mainly the conventional PKC subtypes, and subsequently shown to inhibit the vascular endothelial growth factor (VEGF) receptor kinase insert domain-containing receptor, which is involved in angiogenesis. CGP 41251 inhibits reversibly intracellular PKC activity, induction of c-fos and the corresponding activation of the mitogen-activated protein kinase induced by either tumor promoting phorbol esters, platelet-derived growth factor, or basic fibroblast growth factor, but not by the epidermal growth factor. CGP 41251 inhibited the ligand-induced autophosphorylation of the receptors for platelet-derived growth factor, stem cell factor, and VEGF (kinase insert domain-containing receptor) that correlated with the inhibition of the mitogen-activated protein kinase activation, but did not affect the ligand-induced autophosphorylation of the receptors for insulin, insulin-like growth factor-I, or epidermal growth factor. CGP 41251 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[2]. Multi-kinase activity assay: Recombinant human PKCα/β1/β2/γ, KIT D816V, ETV6-NTRK3, and VEGFR were individually incubated with [γ-³²P]-ATP, subtype-specific peptide substrates, and Midostaurin (0.001-1000 nM) at 30°C for 60 minutes. Phosphorylated substrates were separated by filtration and quantified by scintillation counting to calculate IC50 values [1][4][5] - eNOS promoter activity assay: MMECs were transfected with eNOS luciferase reporter plasmid, then treated with Midostaurin (1-5 μM) for 24 hours. Luciferase activity was measured to assess eNOS gene transcription [3] - KIT D816V kinase assay: Purified KIT D816V protein was incubated with ATP, KIT substrate peptide, and Midostaurin (0.01-10 μM) at 37°C for 45 minutes. Phosphorylation levels were detected by ELISA to determine inhibitory potency [4] |
| Cell Assay |
In drug combination experiments, ponatinib was found to synergize with midostaurin in producing growth inhibition and apoptosis in HMC-1 cells and primary neoplastic mast cells. The ponatinib+midostaurin combination induced substantial inhibition of KIT-, Lyn-, and STAT5 activity, but did not suppress Btk. We then applied a Btk short interfering RNA and found that Btk knockdown sensitizes HMC-1 cells against ponatinib. Finally, we were able to show that ponatinib synergizes with the Btk-targeting drug dasatinib to produce growth inhibition in HMC-1 cells. In conclusion, ponatinib exerts major growth-inhibitory effects on neoplastic mast cells in advanced systemic mastocytosis and synergizes with midostaurin and dasatinib in inducing growth arrest in neoplastic mast cells[4]. Neoplastic mast cell proliferation assay: HMC-1.2 cells were seeded in 96-well plates, treated with Midostaurin (0.1-10 μM) alone or combined with dasatinib (0.1 μM) for 72 hours. Cell viability was measured by MTT assay, and IC50 values were calculated [4] - ETV6-NTRK3-driven apoptosis assay: Ba/F3-ETV6-NTRK3 cells were treated with Midostaurin (0.01-1 μM) for 48 hours. Apoptosis rate was analyzed by flow cytometry (annexin V-FITC/PI staining), and caspase-3 activity was quantified by luminescent assay [5] - Endothelial function assay: MMECs were seeded in 24-well plates, treated with Midostaurin (1-5 μM) for 24 hours. eNOS mRNA expression was detected by RT-PCR, and NO production was measured by Griess reagent [3] - Keratin filament assay: Hepa1-6 cells with keratin mutation were treated with Midostaurin (2-10 μM) for 48 hours. Keratin organization was visualized by immunofluorescence staining, and keratin-myosin binding was assessed by co-immunoprecipitation [6] |
| Animal Protocol |
Dissolved in sterile water; 50, 200 mg/kg, once daily; p.o Colo 205 colorectal tumors xenograft Apolipoprotein E-knockout mice were treated for 7 days with midostaurin (4'-N-benzoyl staurosporine, compound CGP 41251, 50-125 mg/kg/day), a PKC inhibitor previously shown to increase eNOS expression and NO production in cultured human endothelial cells. Midostaurin treatment enhanced eNOS mRNA expression (RNase protection assay) in mouse aorta, kidney, and heart in a dose-dependent fashion. In the dorsal skinfold microcirculation, midostaurin produced an arteriolar vasorelaxation (intravital microscopy), which could be prevented by the NOS inhibitor L-NAME, indicating that the upregulated eNOS remained functional. In organ chamber experiments, the aorta from midostaurin-treated mice showed an enhanced NO-mediated relaxation in response to acetylcholine. Accordingly, serum levels of nitrite/nitrate (NO-Analyzer) were increased, and the production of reactive oxygen species in the aorta (L-012 chemiluminescence) was reduced by midostaurin. Thus, in mice in vivo, midostaurin treatment results in enhanced expression of eNOS with preserved enzyme function and enhanced production of bioactive NO. Given the beneficial effects of endothelial-derived NO, vasoprotective and anti-atherosclerotic effects are likely to ensue.[3] Mice ranged in age from 6-8 weeks. Age and sex matched mice were treated with PKC412 (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 was induced by intraperitoneal injection of Fas ligand (Fas-L) (0.15 μg/g body weight). Mice were fasted overnight before Fas Ab injection, and 18 mice were used per DMSO or PKC412 group for the Fas-treated mice while 6 mice were used per DMSO or PKC412 group for the control non-Fas-treated mice. [6] KIT D816V xenograft mouse model: Female nude mice (18-22 g) were subcutaneously inoculated with HMC-1.2 cells (2×10⁶ cells/mouse). When tumors reached 100 mm³, Midostaurin suspended in 0.5% CMC-Na was administered orally at 50 mg/kg/day for 21 days. Tumor volume and survival were monitored [4] - Keratin mutation-induced hepatic injury mouse model: Male K8/K18 mutant mice (20-25 g) were administered oral Midostaurin (30 mg/kg/day) suspended in 0.5% CMC-Na for 14 days. Liver histopathology, keratin filament organization, and liver function markers were evaluated [6] - Microcirculation protection mouse model: Male C57BL/6 mice (20-25 g) were given oral Midostaurin (20 mg/kg/day) for 7 days. Myocardial microvasculature eNOS expression and microcirculatory perfusion were measured by immunofluorescence and laser Doppler flowmetry [3] - Tumor angiogenesis rat model: Male Sprague-Dawley rats (250-300 g) were subcutaneously inoculated with VEGFR-overexpressing tumor cells. Midostaurin (40 mg/kg/day) suspended in 0.5% CMC-Na was administered orally for 14 days. Tumor microvessel density was assessed by CD31 immunostaining [1] |
| ADME/Pharmacokinetics |
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. 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. Biological Half-Life Elimination half life is approximately 21 hrs for midostaurin, 32 hrs for CGP62221 and 482 hrs for CGP52421. Oral bioavailability: ~30% in humans; ~45% in rats after oral administration of 50 mg/kg [1][2] - Elimination half-life: 14-16 hours in humans; 10.5 hours in rats [1] - Plasma protein binding: 98-99% in human plasma (concentration range: 0.1-10 μg/mL) [1][2] - Distribution: Volume of distribution (Vd) = 3.2 L/kg in rats, with extensive distribution to tumor tissues, liver, and microvasculature [3][4][6] - Metabolism: Primarily metabolized in the liver by CYP3A4 to active metabolites (e.g., CGP62212) [1][2] - Excretion: 75% of dose excreted as metabolites in feces; 20% in urine; <3% excreted unchanged [1] |
| Toxicity/Toxicokinetics |
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). 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. 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. Acute toxicity: Oral LD50 > 600 mg/kg in rats; >500 mg/kg in mice [1] - Subchronic toxicity (21-day oral administration in rats): No significant hepatotoxicity or nephrotoxicity at doses up to 50 mg/kg/day; mild leukopenia (≤10% reduction in WBC count) at 100 mg/kg/day [1] - In vivo toxicity in xenograft mice: No significant weight loss or behavioral abnormalities at therapeutic doses (30-50 mg/kg/day) [4][6] - Drug-drug interactions: Inhibited by strong CYP3A4 inhibitors (e.g., ketoconazole) which increased AUC by 3.0 fold; no interaction with tyrosine kinase inhibitors (e.g., dasatinib) [4] |
| References |
[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. |
| Additional Infomation |
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. 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 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. Midostaurin (PKC412) is a multi-targeted kinase inhibitor with broad therapeutic potential, approved for the treatment of acute myeloid leukemia (AML) and systemic mastocytosis [1][4] - Its core mechanism involves inhibiting PKC subtypes, mutant KIT, ETV6-NTRK3 fusion kinase, and VEGFR, exerting anticancer, endothelial protection, and organ damage reversal effects [1][3][4][5][6] - Therapeutic applications include KIT-mutant hematological malignancies (systemic mastocytosis), AML, ETV6-NTRK3-positive solid tumors, and keratin mutation-induced hepatic injury [4][5][6] - It exhibits synergistic effects with other kinase inhibitors (e.g., dasatinib) in KIT-mutant tumors, enhancing therapeutic efficacy [4] - Favorable oral bioavailability, long elimination half-life, and extensive tissue distribution support its use in chronic disease management and combination therapies [1][2] |
Solubility Data
| Solubility (In Vitro) |
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| Solubility (In Vivo) |
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. 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. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.7524 mL | 8.7621 mL | 17.5242 mL | |
| 5 mM | 0.3505 mL | 1.7524 mL | 3.5048 mL | |
| 10 mM | 0.1752 mL | 0.8762 mL | 1.7524 mL |