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XMD8-92

现货
Catalog No.
A3943
高选择性的BMK1/ERK5抑制剂
组合的产品项目
规格价格库存 数量
10mM (in 1mL DMSO)
¥ 1,100.00
现货
10mg
¥ 750.00
现货
50mg
¥ 3,000.00
现货
100mg
¥ 4,600.00
现货

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Background

IC50: XMD8-92 has been synthesized as a potent inhibitor of Mitogen-activated protein kinase 7 (MAPK7/BMK1; Kd = 80 nM). XMD8-92 blocks EGF-induced activation of BMK1 with IC50 of 240 nM [1].
The mitogen-activated protein kinases (MAPKs) are crucial components of signaling cascades that regulate numerous physiological processes. Four MAPK pathways have been identified thus far, including extracelluar-signal-regulated kinase 1/2 (ERK1/2), c-Jun-amino-terminal kinase (JNK), p38, and BMK1. XMD8-92 is a MAPKs kinase inhibitor with anti-cancer activity against lung and cervical cancers.
In vitro: In a previous study, XMD8-92 was shown to inhibit AsPC-1 cancer cell proliferation and tumor xenograft growth. In XMD8-92 treated tumors, significant downregulation of DCLK1was found and several of its downstream targets, including c-MYC, KRAS, NOTCH1, ZEB1, ZEB2, SNAIL, SLUG, OCT4, SOX2, NANOG, KLF4, LIN28, VEGFR1, and VEGFR2) via upregulation of tumor suppressor miRNAs, such as let-7a, miR-144, miR-200a-c, and miR-143/145. XMD8-92 was, however, not found to affect BMK1 downstream genes p21 and p53. These findings suggested that XMD8-92 treatment led to the inhibition of DCLK1 and downstream oncogenic pathways, which would be a promising chemotherapeutic agent against PDAC [2].
In vivo: In both immunocompetent and immunodeficient mice, XMD8-92 treatment was found to able to block the growth of lung and cervical xenograft tumors, respectively, by 95%. This remarkable anti-tumor effect of XMD8-92 in lung and cervical xenograft tumor models was due to its capacity to inhibit tumor cell proliferation through the PML suppressioninducted p21 checkpoint protein, as well as by blocking of the contribution of BMK1 in tumorassociated angiogenesis [3].
Clinical trial: XMD8-92 is still at preclinical development stage up to this point.
Reference:
[1] Yang Q, Lee JD. Targeting the BMK1 MAP kinase pathway in cancer therapy. Clin Cancer Res. 2011;17(11):3527-32.
[2] Sureban SM, May R, Weygant N, Qu D, Chandrakesan P, Bannerman-Menson E, Ali N, Pantazis P, Westphalen CB, Wang TC, Houchen CW. XMD8-92 inhibits pancreatic tumor xenograft growth via a DCLK1-dependent mechanism. Cancer Lett. 2014;351(1):151-61.
[3] Yang Q, Deng X, Lu B, Cameron M, Fearns C, Patricelli MP, et al. Pharmacological inhibition of
BMK1 suppresses tumor growth through promyelocytic leukemia protein. Cancer Cell. 2010;18:258–67.

文献引用

1. White SM, Avantaggiati ML, et al. "YAP/TAZ Inhibition Induces Metabolic and Signaling Rewiring Resulting in Targetable Vulnerabilities in NF2-Deficient Tumor Cells." Dev Cell. 2019 May 6;49(3):425-443.e9. PMID:31063758

Chemical Properties

Physical AppearanceA solid
StorageStore at -20°C
M.Wt474.57
Cas No.1234480-50-2
FormulaC26H30N6O3
Solubility≥23.75 mg/mL in DMSO, <2.6 mg/mL in EtOH, <2.5 mg/mL in H2O
Chemical Name2-[2-ethoxy-4-(4-hydroxypiperidin-1-yl)anilino]-5,11-dimethylpyrimido[4,5-b][1,4]benzodiazepin-6-one
SDFDownload SDF
Canonical SMILESCCOC1=C(C=CC(=C1)N2CCC(CC2)O)NC3=NC=C4C(=N3)N(C5=CC=CC=C5C(=O)N4C)C
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]:

细胞系

人胰腺肿瘤细胞系(AsPC-1)

溶解方法

在DMSO中的溶解度> 23.8 mg/ml。为了获得更高浓度,可以将离心管在37℃加热10分钟和/或在超声波浴中震荡一段时间。原液可以在-20℃以下储存几个月。

反应条件

10和15 μM孵育48小时

应用

在用10和15μM的XMD8-92处理后,在AsPC-1中DCLK1 mRNA和蛋白质呈剂量依赖性下调。 此外,还发现用XMD8-92处理的AsPC-1细胞中c-MYC、KRAS和NOTCH1 mRNA有着近60%的减少。 这些数据表明,用XMD8-92处理AsPC-1细胞会造成DCLK1、c-MYCKRAS和NOTCH1 mRNA的下调。

动物实验 [1]:

动物模型

HeLa, A549 以及 LL/2荷瘤小鼠模型

剂量

50 mg/kg,一天两次

应用

研究发现XMD8-92治疗不仅能阻止肿瘤生长,还能减少肿瘤体积,而溶媒处理的肿瘤在整个实验中呈指数级增长。 此外,与对照肿瘤相比,XMD8-92治疗能造成肿瘤体积的显著降低(> 80%)。 与此同时,该研究还观察到经XMD8-92处理后肿瘤重量减少了2倍以上。

注意事项

请测试所有化合物在室内的溶解度,实际溶解度和理论值可能略有不同。这是由实验系统的误差引起的,属于正常现象。

References:

[1] Sureban SM et al. XMD8-92 inhibits pancreatic tumor xenograft growth via a DCLK1-dependent mechanism. Cancer Lett. 2014 Aug 28;351(1):151-61.

生物活性

描述 XMD8-92 是一种强效的和选择性的BMK1/ERK5抑制剂,Kd值为80 nM。
靶点 BMK1/ERK5          
IC50 Kd=80 nM          

质量控制

化学结构

XMD8-92