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LY2109761TβRI/II激酶抑制剂

LY2109761

产品编号:A8464
ApexBio 的所有产品仅用作科研,我们不为任何个人用途提供产品和服务
规格 单价 库存 订购数量
10mM (in 1mL DMSO) ¥2,500.00 现货
5mg ¥1,750.00 现货
10mg ¥2,600.00 现货
50mg ¥7,800.00 现货

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Sample solution is provided at 25 µL, 10mM.

引用文献

1. Yang H, Li W, et al. "Regulatory role of miR-18a to CCN2 by TGF-β1 signaling pathway in pulmonary injury induced by nano-SiO(2)." Environ Sci Pollut Res Int. 2017 Oct 24. PMID:29067610
2. Singh SK, Fiorelli R, et al. "Post-translational Modifications of OLIG2 Regulate Glioma Invasion through the TGF-β Pathway." Cell Rep. 2016 Jul 26;16(4):950-66. PMID:27396340
3. Llobet-Navas, David, et al. "The miR-424/503 cluster reduces CDC25A expression during cell cycle arrest imposed by TGFβ in mammary epithelial cells." Molecular and Cellular Biology (2014): MCB-00611. PMID:25266660

质量控制

相关生物数据

LY2109761
Administration of LY2109761 partially inhibits mammary epithelial regression as measured by whole mount Carmine Red staining (A) and quantification by qRT-PCR of milk proteins α-lactalbumin (LALBA), whey-acidic protein (WAP) and β-casein (CSN2) in purified mammary epithelial cells (B). Western blot showing increased protein levels of CDC25A in mammary epithelial cells treated with LY2109761 (C).

相关生物数据

LY2109761
C:inhibition of P-Smad2 levels by LY2109761 was determined by Western blot analysis of lung tissue from mice after a single oral dose of 100mg/kg LY2109761.D:tumor-bearing mice that had been subjected to thrice daily oral dosing with LY2109761 at 100mg/mL for 10 days(short term) were administered an additional oral bolus of 100mg/kg LY2109761 and protein lysates from papilloma,carcinoma,and lung were isolated 2 hours later.Western blot analysis was carried out to detect P-Smad2,total Smad2,and b -actin levels C,inhibition of P-Smad2 levels by LY2109761 was determined by Western blot analysis of lung.

相关生物数据

LY2109761

相关生物数据

LY2109761

相关生物数据

LY2109761

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化学性质

CAS号 700874-71-1 SDF Download SDF
化学名 4-[2-[4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)quinolin-7-yl]oxyethyl]morpholine
SMILES C1CC2=C(C(=NN2C1)C3=CC=CC=N3)C4=C5C=CC(=CC5=NC=C4)OCCN6CCOCC6
分子式 C26H27N5O2 分子量 441.52
溶解度 ≥22.1mg/mL in DMSO 储存条件 Store at -20°C
物理性状 A solid 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。

生物活性

描述 LY2109761是一种新型的选择性I/II型TGF-β受体(TβRI/II)抑制剂,Ki值分别为38 nM和300 nM。
靶点 TβRI TβRII        
IC50 38 nM (Ki) 300 nM (Ki)        

实验操作

细胞实验[1]:

细胞系

人类MDA PCa 2b、PC-3细胞系

溶解方法

在DMSO中的溶解度<10 mM。为了获得更高的浓度,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

24 h;4 μM

应用

受体激活的Smad2和Smad3的磷酸化是TGF-β1信号转导中一个重要的步骤。在rhTGF-β1处理的MDA PCa 2b细胞、PC-3细胞和PMOs裂解物中,TGF-β1诱导PC-3和PMOs,而非MDA PCa 2b细胞中Smad2的磷酸化。而且,LY2109761可以逆转rhTGF-β1诱导的Smad2的磷酸化。换句话说,LY2109761抑制PC-3和PMOs细胞中TGF-β1诱导的Smad2的激活。

动物实验[1]:

动物模型

雄性SCID小鼠

剂量

200 mg/kg/day;口服给药

应用

3周治疗之后,对照组的X射线分析显示有两处骨折,在荷瘤骨段减少了30%-70%的放射不透过性区域。MRI分析表明,治疗组比对照组有显著更小的肿瘤体积(p=0.012)。对照组和治疗组中荷瘤骨段的微CT分析表明,对照小鼠有显著更低的BV(p=0.00043)、BMC(p =0.000132)和BMD(p = 0.000085)。而且,治疗组的BV、BMC和BMD均恢复到正常股骨(未注射)中水平,支持了LY2109761的治疗效应。最后,骨组织形态学分析表明,LY2109761抑制PC-3诱导的破骨细胞的活化。

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] Wan X, Li Z G, Yingling J M, et al. Effect of transforming growth factor beta (TGF-β) receptor I kinase inhibitor on prostate cancer bone growth[J]. Bone, 2012, 50(3): 695-703.

产品描述

LY2109761是一种选择性的I/II型TGF-β受体(TβRI/II)小分子抑制剂,Ki值分别为38 nM和300 nM[1]。在TβRI 酶实验中,IC50值为69 nM。晶体结构显示LY2109761与TGF-βR1激酶结构域的ATP结合位点相结合。LY2109761对其它的激酶(包括Lck、Sapk2α、MKK6、Fyn和JNK3)具有较弱的抑制活性(20 μM时18-89%的抑制)[2]。

在临床前研究中,LY2109761具有潜在的抗肿瘤活性。TGF-β信号通路的调控缺失与各种恶性肿瘤的发生相关。在胰腺癌细胞中,LY2109761抑制细胞增殖、迁移和侵袭,诱导细胞凋亡。在转移性胰腺癌小鼠模型中,LY2109761与gemcitabine联合给药抑制肿瘤生长和转移[1]。在骨髓 - 单核细胞白血病细胞中,LY2109761抑制TGF-beta1的抗凋亡效应[3]。在胶质母细胞瘤(GBM)细胞系和原位颅内移植模型中,LY2109761增加放射敏感性,导致存活期的延长[4]。此外,在小鼠模型中,LY2109761减少放射诱导的肺炎和肺纤维化[5]。

参考文献:
[1]Melisi D, Ishiyama S, Sclabas GM et al.  LY2109761, a novel transforming growth factor beta receptor type I and type II dual inhibitor, as a therapeutic approach to suppressing pancreatic cancer metastasis. Mol Cancer Ther 2008; 7: 829-840.
[2]Li HY, McMillen WT, Heap CR et al.  Optimization of a dihydropyrrolopyrazole series of transforming growth factor-beta type I receptor kinase domain inhibitors: discovery of an orally bioavailable transforming growth factor-beta receptor type I inhibitor as antitumor agent. J Med Chem 2008; 51: 2302-2306.
[3]Xu Y, Tabe Y, Jin L et al.  TGF-beta receptor kinase inhibitor LY2109761 reverses the anti-apoptotic effects of TGF-beta1 in myelo-monocytic leukaemic cells co-cultured with stromal cells. Br J Haematol 2008; 142: 192-201.
[4]Zhang M, Kleber S, Rohrich M et al.  Blockade of TGF-beta signaling by the TGFbetaR-I kinase inhibitor LY2109761 enhances radiation response and prolongs survival in glioblastoma. Cancer Res 2011; 71: 7155-7167.
[5]Flechsig P, Dadrich M, Bickelhaupt S et al.  LY2109761 attenuates radiation-induced pulmonary murine fibrosis via reversal of TGF-beta and BMP-associated proinflammatory and proangiogenic signals. Clin Cancer Res 2012; 18: 3616-3627.