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Midostaurin (PKC412)

现货
Catalog No.
B3709
PKC抑制剂
组合的产品项目
规格价格库存 数量
1mg
¥ 500.00
现货
5mg
¥ 1,350.00
现货
10mg
¥ 2,100.00
现货
25mg
¥ 4,200.00
现货

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Background

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.

Chemical Properties

Physical AppearanceA solid
StorageStore at -20°C
M.Wt570.64
Cas No.120685-11-2
FormulaC35H30N4O4
Solubility≥57.1mg/mL in DMSO with ultrasonic
SDFDownload SDF
Canonical SMILESCC12C(C(CC(O1)N3C4=CC=CC=C4C5=C6C(=C7C8=CC=CC=C8N2C7=C53)CNC6=O)N(C)C(=O)C9=CC=CC=C9)OC
运输条件试用装:蓝冰运输。 其他可选规格:常温运输或根据您的要求用蓝冰运输。
一般建议为了使其更好的溶解,请用37℃加热试管并在超声波水浴中震动片刻。不同厂家不同批次产品溶解度各有差异,仅做参考。若实验所需浓度过大至产品溶解极限,请添加助溶剂助溶或自行调整浓度。

试验操作

细胞实验[1-3]:

细胞系

Ba/F3-FLT3-ITD细胞,Ba/F3细胞,M0-91和IMS-M2细胞

溶解方法

该化合物在DMSO中的溶解度大于10 mM。若获取更高浓度的溶液,可在37℃下孵育10分钟,随后在超声波浴中摇匀。-20℃以下可储存数月。

反应条件

0.01–1 μM,24–72 hr

应用

PKC412对各种肿瘤和正常细胞系具有广泛的抗增殖活性,能够逆转肿瘤细胞中Pgp介导的多药耐药性。PKC412以剂量依赖性方式增加细胞周期G2/M期,伴随多倍体增多、细胞凋亡和对电离辐射的敏感性增强。在24-72小时内PKC412抑制Ba/F3-FLT3-ITD细胞的增殖,IC50低于10 nM,在浓度高达100 nM时对亲本Ba/F3细胞无毒性。PKC412抑制Ba/F3-FLT3-D835Y细胞的增殖和活力。在Ba/F3-FLT3-ITD和Ba/F3-FLT3-D835Y细胞中,PKC412(0.01-1 μM,15min)有效抑制FLT3酪氨酸磷酸化。在Ba/F3-FLT3-ITD细胞中,用高达0.04 μM的PKC412处理两个月,生成对PKC412不太敏感的Ba/F3-FLT3-ITD细胞的多克隆亚系。在造血性Ba/F3细胞中,PKC412抑制EN融合酪氨酸激酶。PKC412以剂量依赖的方式显著抑制M0-91和IMS-M2细胞的EN磷酸化

动物实验 [1,2,4]:

动物模型

FLT3/ITD诱导的骨髓增生性疾病(MPD)Balb/c小鼠

给药剂量

口服,100 mg/kg

应用

在对电离辐射和化疗剂(功能障碍p53)具有抗性的肿瘤中,PKC412与局部电离辐射的组合使用具有显著的抗肿瘤活性。口服PKC412强烈抑制视网膜新血管形成以及激光诱导的鼠模型中的脉络膜新生血管形成。在FLT3/ITD诱导的骨髓增生性疾病(MPD)的Balb/c小鼠中,PKC412延长存活。PKC412抑制FLT3-ITD介导的转化。在小鼠中,PKC412处理仅轻微增加平均脾脏重量(80 mg)。腹腔注射PKC412(25 mg/kg)保护表达突变体或野生型K18的培养A549细胞和过表达K18 Arg90Cys的转基因小鼠的肝脏免受Fas诱导的凋亡。

注意事项

由于实验环境的不同,实际溶解度可能与理论值略有不同,请测试室内所有化合物的溶解度。

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.

生物活性

Description Midostaurin是多种丝氨酸/苏氨酸和酪氨酸激酶的细胞透过性可逆抑制剂.
靶点 PKCα VEGFR PDFRβ Syk Flk-1 Flt3
IC50 22 nM 1 μM        

质量控制

化学结构

Midostaurin (PKC412)