Midostaurin (PKC412)
(Synonyms: 米哚妥林; PKC412; CGP 41251) 目录号 : GC10496
Midostaurin (PKC412)是一种口服多靶点酪氨酸激酶抑制剂，可抑制多种激酶，包括FLT3、KIT、PDGFR 和 VEGFR（IC50 = 22-500nM）。
Cas No.:120685-11-2
Sample solution is provided at 25 µL, 10mM.
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Midostaurin (PKC412) is an oral, multi-targeted tyrosine kinase inhibitor that inhibits multiple kinases, including FLT3, KIT, PDGFR, and VEGFR (IC50 = 22-500nM) [1-2]. Midostaurin competitively inhibits the binding of ATP to kinases, thereby blocking tumor cell proliferation and promoting apoptosis [3]. Midostaurin is commonly used to treat acute myeloid leukemia (AML) harboring FLT3 mutations [4].
In peripheral blood mononuclear cells (PBMCs), Midostaurin (1µM; 72h) significantly reduced the CD4+CD25+FOXP3+ T cell population and FOXP3 mRNA expression in PBMCs [5]. In MDA -MB-468 cells, Midostaurin (1µM; 72h) directly inhibits Aurora kinases A and B and subsequently reduces cell viability in TNBC cells [6]. In HMC-1 cells, ponatinib cooperates with Midostaurin (0-0.1µM; 48h) to induce growth inhibition and apoptosis [7].
In CT26 cells xenograft tumor mouse model, Midostaurin (100mg/kg; po; 7d) treatment significantly inhibited tumor growth [8]. In HL-60 cells xenograft tumor mouse model, All-trans retinoic acid combined with Midostaurin (50mg/kg; po; 10d) treatment significantly inhibited tumor growth [9].
References:
[1]. Fabbro D, Buchdunger E, Wood J, et al. Inhibitors of protein kinases: CGP 41251, a protein kinase inhibitor with potential as an anticancer agent[J]. Pharmacology & therapeutics, 1999, 82(2-3): 293-301.
[2]. Fabbro D, Ruetz S, Bodis S, et al. PKC412-a protein kinase inhibitor with a broad therapeutic potential[J]. Anti-cancer drug design, 2000, 15(1): 17-28.
[3]. Gallogly M M, Lazarus H M, Cooper B W. Midostaurin: a novel therapeutic agent for patients with FLT3-mutated acute myeloid leukemia and systemic mastocytosis[J]. Therapeutic advances in hematology, 2017, 8(9): 245-261.
[4]. Levis M. Midostaurin approved for FLT3-mutated AML[J]. Blood, The Journal of the American Society of Hematology, 2017, 129(26): 3403-3406.
[5]. Gutierrez L, Jang M, Zhang T, et al. Midostaurin reduces regulatory T cells markers in acute myeloid leukemia[J]. Scientific reports, 2018, 8(1): 17544.
[6]. Kawai M, Nakashima A, Kamada S, et al. Midostaurin preferentially attenuates proliferation of triple-negative breast cancer cell lines through inhibition of Aurora kinase family[J]. Journal of biomedical science, 2015, 22(1): 48.
[7]. Gleixner K V, Peter B, Blatt K, et al. Synergistic growth-inhibitory effects of ponatinib and midostaurin (PKC412) on neoplastic mast cells carrying KIT D816V[J]. Haematologica, 2013, 98(9): 1450.
[8]. Lai C T, Chi C W, Wu S H, et al. Midostaurin modulates tumor microenvironment and enhances efficacy of anti-PD-1 against colon cancer[J]. Cancers, 2022, 14(19): 4847.
[9]. Lu H, Weng X, Sheng Y, et al. Combination of midostaurin and ATRA exerts dose-dependent dual effects on acute myeloid leukemia cells with wild type FLT3[J]. BMC cancer, 2022, 22(1): 749.
Midostaurin (PKC412)是一种口服多靶点酪氨酸激酶抑制剂，可抑制多种激酶，包括FLT3、KIT、PDGFR 和 VEGFR（IC50 = 22-500nM） [1-2]。Midostaurin竞争性地抑制ATP与激酶的结合，从而阻止肿瘤细胞增殖并促进细胞凋亡 [3]。Midostaurin常用于治疗携带FLT3突变的急性髓系白血病（AML） [4]。
在外周血单核细胞（PBMC）中，Midostaurin（1µM；72h）显著降低CD4+CD25+FOXP3+T细胞群和FOXP3 mRNA的表达 [5]。在MDA-MB-468细胞中，Midostaurin（1µM；72h）直接抑制Aurora激酶A和B，从而降低TNBC细胞的细胞活力 [6]。在HMC-1细胞中，普纳替尼与Midostaurin（0-0.1µM；48h）协同作用，导致生长抑制和细胞凋亡 [7]。
在CT26细胞异种移植瘤小鼠模型中，Midostaurin（100mg/kg；po；7d）治疗显著抑制肿瘤生长 [8]。在HL-60细胞异种移植瘤小鼠模型中，全反式维甲酸联合Midostaurin（50mg/kg；po；10d）治疗显著抑制肿瘤生长 [9]。
| Cell experiment [1]: | |
Cell lines | Peripheral blood mononuclear cells (PBMCs) |
Preparation Method | PBMCs were cultured in Roswell Park Memorial Institute 1640 1x (RPMI) medium supplemented with 20% fetal bovine serum (FBS). In addition, PBMCs were treated with IL-2 (5ng/mL) and IL-7 (10ng/mL), as well as 1µM of Midostaurin. PBMCs were seeded at 2 million cells per well in a 6 well plate, and allowed to incubate at 5% CO2, 37 ℃ for 72 hours before analysis via flow cytometry or quantitative polymerase chain reaction. |
Reaction Conditions | 1µM; 72h |
Applications | Midostaurin reduces CD4 + CD25 + FOXP3 + T cell population in healthy PBMC. |
| Animal experiment [2]: | |
Animal models | CT26 cells xenograft tumor mouse model |
Preparation Method | Male BALB/c mice at five weeks old were purchased from the National Laboratory Animal Center of Taiwan and housed under 12-h light/dark cycle under a specific pathogen-free facility. The 4 × 106 CT26 cells in 100μL PBS were subcutaneously inoculated on the right hindlimb of the mice. After the tumors grew for 7 days to achieve a mean diameter of approximate 5mm, mice were randomly allocated into 4 groups as follows: (1) control, (2) Midostaurin (100mg/kg), (3) intraperitoneal anti-PD-1 injection (200μg), and (4) Midostaurin in combination with anti-PD-1. |
Dosage form | 100mg/kg; po; 7d |
Applications | Midostaurin treatment significantly inhibited tumor growth. |
References: | |
| Cas No. | 120685-11-2 | SDF | |
| 别名 | 米哚妥林; PKC412; CGP 41251 | ||
| Canonical SMILES | CC12C(C(CC(O1)N3C4=CC=CC=C4C5=C6C(=C7C8=CC=CC=C8N2C7=C53)CNC6=O)N(C)C(=O)C9=CC=CC=C9)OC | ||
| 分子式 | C35H30N4O4 | 分子量 | 570.64 |
| 溶解度 | ≥ 57.1mg/mL in DMSO with ultrasonic | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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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 |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Quality Control & SDS
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- Purity: >98.00%
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