LY2109761

生物活性

LY2109761是一种新型的，选择性的TGF-β receptor type I/II (TβRI/II)双重抑制剂，K_i分别为38 nM和300 nM，对Smad2的磷酸化产生负面影响。LY2109761 处理FG/GLT或L3.6pl/GLT单层细胞生长，没有抗增殖效果，但是显著抑制L3.6pl/GLT细胞低贴壁生长，这种作用存在剂量依赖性，按2 μM 和 20 μM处理，则抑制分别为~33% 和73%, 与 Gemcitabine联用可强增强这种效果。LY2109761(5 μM)阻断TβRI/II激酶活性，完全抑制基础型和TGF-β1刺激的L3.6pl/GLT cells细胞迁移和入侵,显著增强脱离诱导的凋亡，处理8小时，凋亡达 26%，且完全抑制TGF-β诱导的Smad2磷酸化。 1 nM LY2109761通过提高E-钙粘蛋白表达，而显著阻断迁移和入侵，而不会抑制肝癌细胞的粘附。

实验操作 来自于公开的文献，仅供相同实验参考（如实验材料、目的不同，请参考其他文献）

细胞实验
细胞系	Colo357FG/GLT and Colo357L3.6pl/GLT cells
方法	LY2109761 was dissolved in 100% DMSO at a stock concentration of 10 mmol/L. The concentration of DMSO did not exceed 0.1% in any assay. FG/GLT nonmetastatic pancreatic carcinoma cells (A) and their highly metastatic subclone L3.6pl/GLT pancreatic carcinoma cells were seeded at a density of 1.0 × 103 per well. On the following day, the cells were treated with increasing doses of LY2109761 (0.1, 1, and 10 μmol/L), gemcitabine (0.3, 3,and 30 nmol/L), and their combinations. On day 2, the medium containing drugs was removed, the cells were washed twice with PBS, and fresh medium was added. After 5 d of incubation, the 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay was used to obtain relative variable cell numbers. DMSO-treated cells were assigned a value of 100%. Means and 95% confidence intervals of three independent experiments performed in triplicate.
浓度	0, 2, 20 µ M
处理时间	5 days

动物实验
动物模型	Human Pancreatic Carcinoma Tumors Growing in the Pancreas of Athymic Nude Mice
配制	dissolved in the SX-1292 oral vehicle (1% sodium carboxymethylcellulose, 0.5% sodium lauryl sulfate, and 0.05% antifoam; Eli Lilly)
剂量	LY2109761 (50 mg/kg) twice a day p.o. (days 1–5 of each week)
给药处理	p.o.

不同实验动物依据体表面积的等效剂量转换表（数据来源于FDA指南）

	小鼠	大鼠	兔	豚鼠	仓鼠	狗
重量 (kg)	0.02	0.15	1.8	0.4	0.08	10
体表面积 (m2)	0.007	0.025	0.15	0.05	0.02	0.5
Km 系数	3	6	12	8	5	20

动物 A (mg/kg) = 动物 B (mg/kg) ×	动物 B的Km系数
	动物 A的Km系数

例如，依据体表面积折算法，将白藜芦醇用于小鼠的剂量22.4 mg/kg 换算成大鼠的剂量，需要将22.4 mg/kg 乘以小鼠的K_m系数（3），再除以大鼠的K_m系数（6），得到白藜芦醇用于大鼠的等效剂量为11.2 mg/kg。

化学数据

储备液配制

以下数据基于产品分子量，对于特殊产品，请参照COA中的储备液配制条件和说明进行操作。

Concentration / Solvent Volume / Mass	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

使用AbMole产品发表的文献

• 

  Brain Res Bull. 2020 May 8;161:21-32.

  TGFβ1 Alleviates Axonal Injury by Regulating Microglia/Macrophages Alternative Activation in Traumatic Brain Injury
  LY2109761购买自AbMole

• 

  Int Immunopharmacol. 2018 Dec 17;67:287-293.

  Effect of recombinant human thrombopoietin on immune thrombocytopenia in pregnancy in a murine model.
  LY2109761购买自AbMole

客户产品验证及相关生物数据

	数据来源	Dissertaion (2015). Figure 3.5. LY2109761 was obtained from abmole (AbMole, Houston, TX).
	方法	western blot
	细胞系	mesenchymal/stem cell tumor
	浓度	50mg/kg LY2109761 twice every day
	处理时间	two weeks
	实验结果	LY2109761 significantly decreased the expression levels of ZEB2, VCAN, THY1, CDK6, SOX2 and GLI2, even in the presence of TMZ/IR, demonstrating the key role of the TGF-β signaling pathway in regulating mesenchymal and stem cells markers.

参考文献

Blockade of TGF-β signaling by the TGFβR-I kinase inhibitor LY2109761 enhances radiation response and prolongs survival in glioblastoma.
Zhang M, et al. Cancer Res. 2011 Dec 1;71(23):7155-67. PMID: 22006998.

Trimodal glioblastoma treatment consisting of concurrent radiotherapy, temozolomide, and the novel TGF-β receptor I kinase inhibitor LY2109761.
Zhang M, et al. Neoplasia. 2011 Jun;13(6):537-49. PMID: 21677877.

LY2109761, a novel transforming growth factor beta receptor type I and type II dual inhibitor, as a therapeutic approach to suppressing pancreatic cancer metastasis.
Melisi D, et al. Mol Cancer Ther. 2008 Apr;7(4):829-40. PMID: 18413796.