LY2109761
目录号 : GC12363
A dual inhibitor of TGF-β type 1/type II receptor kinases
Cas No.:700874-71-1
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >99.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
| Cell experiment [1]: | |
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Cell lines |
Human cell MDA PCa 2b, PC-3 lines. |
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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 °C for 10 minutes and/or shake it in the ultrasonic bath for a while.Stock solution can be stored below -20°C for several months.. |
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Reacting condition |
24h; 4 μM |
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Applications |
A crucial step in the transduction of TGF-β 1 signals is the phosphorylation of receptor-activated Smad2 and Smad3. We thus assessed the phosphorylation of Smad2 in lysates of MDA PCa 2b cells, PC-3 cells, and PMOs treated with rhTGF- β1. We found that TGF-β1 induces phosphorylation of Smad2 in PC-3 cells and PMOs but not in MDA PCa 2b cells. Further, treatment with LY2109761 reverses the Smad2 phosphorylation induced by rhTGF-β1. In other words, LY2109761 inhibits TGF-β1–induced Smad2 activation in PC-3 cells and PMOs. |
| Animal experiment [1]: | |
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Animal models |
Male SCID mice |
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Dosage form |
200 mg/kg/day; oral taken |
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Application |
After 3 weeks of treatment, X-ray analysis of the vehicle control group revealed two broken bones and loss of 30%–70% of the radiopaque areas in the tumor-bearing bones. MRI analysis showed a significantly smaller tumor volume in the treated group than in the controls (p =0.012). Micro-CT analysis of the tumor-bearing bones of the controls and treated mice demonstrated significantly lower BV (p=0.00043), BMC (p =0.000132), and BMD (p = 0.000085) in the control mice. Furthermore, BV, BMC, and BMD in the treated group were restored to values found in the normal (uninjected) femurs, which supports the efficacy of treatment. Finally, bone histomorphometric analysis demonstrated that LY2109761 inhibited PC-3-induced activation of osteoclasts. |
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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] 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. | |
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.
| Cas No. | 700874-71-1 | 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 | ||
| Canonical 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 |
| 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 | 2.2649 mL | 11.3245 mL | 22.649 mL |
| 5 mM | 0.453 mL | 2.2649 mL | 4.5298 mL |
| 10 mM | 0.2265 mL | 1.1325 mL | 2.2649 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。