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LY2109761

现货
Catalog No.
A8464
TβRI/II激酶抑制剂
组合的产品项目
规格价格库存 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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Background

LY2109761 is a small-molecule inhibitor selectively targeting both TGF-β receptor type I and II ((TβRI/II)) with Ki of 38 nM and 300 nM, respectively [1]. It gave IC50 value of 69 nM in TβRI enzymatic assay [2]. Crystal structure showed the binding of LY2109761 to the ATP binding site of the TGF-β R1 kinase domain [2]. Weak inhibitory activities were reported for other kinases, including Lck, Sapk2α, MKK6, Fyn, and JNK3 (18–89% inhibition at 20 µM) [2].

LY2109761 has shown potential anti-tumor activity in preclinical studies. Deregulation of TGF-β signaling pathway is correlated with various malignant. LY2109761 suppressed proliferation, migration and invasion, and induced apoptosis of pancreatic cancer cells [1]. When combined with gemcitabine, it inhibited tumor growth and metastasis in a mouse model of metastatic pancreatic cancer [1]. It also inhibited the anti-apoptotic effects of TGF-beta1 in myelo-monocytic leukaemic cells [3]. Results in GBM cell lines and an orthotopic intracranial model indicated that LY2109761 increased radiosensitivity and resulted in prolonged survival in glioblastoma [4]. In addition, LY2109761 reduced radiation-induced pneumonitis and pulmonary fibrosis in a murine model [5].

References:
[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.

文献引用

1. Song Y, Chen Y, et al. "Resveratrol Suppresses Epithelial-Mesenchymal Transition in GBM by Regulating Smad-Dependent Signaling." Biomed Res Int. 2019 Apr 7;2019:1321973. PMID:31119150
2. 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
3. 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
4. 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

Chemical Properties

Physical AppearanceA solid
StorageStore at -20°C
M.Wt441.52
Cas No.700874-71-1
FormulaC26H27N5O2
Solubility≥22.1mg/mL in DMSO
Chemical Name4-[2-[4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)quinolin-7-yl]oxyethyl]morpholine
SDFDownload SDF
Canonical SMILESC1CC2=C(C(=NN2C1)C3=CC=CC=N3)C4=C5C=CC(=CC5=NC=C4)OCCN6CCOCC6
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.

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)        

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