Midostaurin (PKC412)
(Synonyms: 米哚妥林; PKC412; CGP 41251) 目录号 : GC10496
Kinase inhibitor with potential use in cancer treatment
Cas No.:120685-11-2
Sample solution is provided at 25 µL, 10mM.
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Midostaurin is an inhibitor of PKC with IC50 values of 22nM, 30nM, 31nM, 24nM, 330nM, 160nM and 1.25μM for PKC-α, PKC-β1, PKC-β2, PKC-γ, PKC-δ, PKC-η and PKC-ε, respectively [1].
Midostaurin is a PKC inhibitor with potent activity against most PKC subtypes. It also has inhibitory activity against KDR and its mouse homologue Flk-1. Other protein kinases involved in angiogenesis, cell cycle and cell growth are not sensitive to midostaurin. Midostaurin shows reversible inhibition of intracellular PKC activity with IC50 value of 0.5μM. Besides PKC, midostaurin inhibits the autophosphorylation of the receptors for PDGF, VEGF and stem cell factor with IC50 values of 80nM, 1μM and 30nM, respectively. Midostaurin also inhibits the FGF-induced c-fos transcription and MAPK activation. Moreover, midostaurin suppresses cell growth of different cell lines through inducing cell cycle arrest in G2/M and inducing apoptosis [1].
Furthermore, midostaurin exerts antitumor activity via inhibiting tumor angiogenesis and proliferation due to its effects on VEGFR and PKC, respectively. Administration of midostaurin prolongs the life span of mice bearing B16 melanoma at dose of 75mg/kg 3 times daily for 9 days [1].
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. Pharmacology & therapeutics, 1999, 82(2): 293-301.
| Cell experiment [1-3]: | |
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Cell lines |
Ba/F3-FLT3-ITD cells, Ba/F3 cells, M0-91 and IMS-M2 cells |
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Preparation method |
The solubility of this compound in DMSO is > 10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37 ℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months. |
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Reacting condition |
0.01–1 μM, 24–72 hr |
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Applications |
PKC412 showed a broad antiproliferative activity against various tumor and normal cell lines in vitro, and was able to reverse the Pgp-mediated multidrug resistance of tumor cells. PKC412 resulted in a dose-dependent increase in the G2/M phase of the cell cycle concomitant with increased polyploidy, apoptosis and enhanced sensitivity to ionizing radiation. PKC412 inhibited the proliferation of Ba/F3-FLT3-ITD cells with an IC50 of less than 10 nM within 24–72 hr, and was nontoxic toward parental Ba/F3 cells at concentrations up to 100 nM. PKC412 inhibited proliferation and viability of Ba/F3-FLT3-D835Y cells. PKC412 (0.01–1 μM, 15 min) potently inhibited FLT3 tyrosine phosphorylation in Ba/F3-FLT3-ITD and Ba/F3-FLT3-D835Y cells. In Ba/F3-FLT3-ITD cells, treatment with PKC412 (up to 0.04 μM) over a span of two months generated a polyclonal subline of Ba/F3-FLT3-ITD cells less sensitive to PKC412. PKC412 inhibited EN fusion tyrosine kinase in hematopoietic Ba/F3 cells. PKC412 significantly inhibited EN phosphorylation in M0-91 and IMS-M2 cells in a dose-dependent manner. |
| Animal experiment [1,2,4]: | |
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Animal models |
Balb/c mice with FLT3/ITD-induced myeloproliferative disorder (MPD) |
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Dosage form |
Oral administration, 100 mg/kg |
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Application |
Combination 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). Orally administered PKC412 strongly inhibited retinal neovascularization as well as laser-induced choroidal neovascularization in murine models. In Balb/c mice with FLT3/ITD-induced myeloproliferative disorder (MPD), PKC412 prolonged survival. PKC412 inhibited FLT3-ITD-mediated transformation. PKC412-treated mice displayed only a slight increase in mean spleen weight (80 mg). PKC412 (25 mg/kg, i.p.) protected cultured A549 cells that expressed mutant or wild-type K18 and mouse livers of the K18 Arg90Cys-overexpressing transgenic mice from Fas-induced apoptosis. |
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Other notes |
Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal. |
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References: [1]. 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. [2]. Weisberg E, Boulton C, Kelly L M, et al. Inhibition of mutant FLT3 receptors in leukemia cells by the small molecule tyrosine kinase inhibitor PKC412[J]. Cancer cell, 2002, 1(5): 433-443. [3]. Chi HT, et al. ETV6-NTRK3 as a therapeutic target of small molecule inhibitor PKC412. Biochem Biophys Res Commun. 2012 Dec 7;429(1-2):87-92. [4]. Juarez JC, et al. Copper binding by tetrathiomolybdate attenuates angiogenesis and tumor cell proliferation through the inhibition of superoxide dismutase 1. Clin Cancer Res. 2006 Aug 15;12(16):4974-82. |
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| 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
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet