LY2109761 is a Transforming Growth Factor β (TGF-β) type I /II receptor (TβRI/TβRII) kinase inhibitor with Ki of 38 nM and 300 nM, respectively. LY2109761 significantly inhibited the L3.6pl/GLT soft agar growth, suppressed both basal and TGF-beta1-induced cell migration and invasion, and induced anoikis. LY2109761 reduced clonogenicity and increased radiosensitivity in GBM cell lines and cancer stem-like cells, augmenting the tumor growth delay produced by fractionated radiotherapy in a supra-additive manner in vivo. In addition, LY2109761 had antimigratory and antiangiogenic effects in Matrigel migration and tube formation assays. LY2109761 also reduced tumor blood perfusion as quantified by noninvasive dynamic contrast-enhanced magnetic resonance imaging. In an orthotopic intracranial model, LY2109761 significantly reduced tumor growth, prolonged survival, and extended the prolongation of survival induced by radiation treatment. In vivo, in human xenograft tumors growing subcutaneously on BALB/c nu/nu mice, LY2109761 delayed tumor growth alone and in combination with fractionated radiation and TMZ.
|Cell lines||Colo357FG/GLT and Colo357L3.6pl/GLT cells|
|Preparation method||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.|
|Concentrations||0, 2, 20 µ M|
|Incubation time||5 days|
|Animal models||Human Pancreatic Carcinoma Tumors Growing in the Pancreas of Athymic Nude Mice|
|Formulation||dissolved in the SX-1292 oral vehicle (1% sodium carboxymethylcellulose, 0.5% sodium lauryl sulfate, and 0.05% antifoam; Eli Lilly)|
|Dosages||LY2109761 (50 mg/kg) twice a day p.o. (days 1–5 of each week)|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
|Source||Dissertaion (2015). Figure 3.5. LY2109761 was obtained from abmole (AbMole, Houston, TX).|
|Cell Lines||mesenchymal/stem cell tumor|
|Concentrations||50mg/kg LY2109761 twice every day|
|Incubation Time||two weeks|
|Results||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.|
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.
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