LY2109761

SKU: orb1306433

Description

LY2109761 is a potent and selective dual inhibitor of TGF-β receptor types I and II (TβRI/II), with respective Ki values of 38 nM and 300 nM. It effectively blocks Smad2 phosphorylation and is widely used in vitro and in vivo to study TGF-β signaling in cancer, fibrosis, and immunology research.

Research Area

Cell Biology, Stem Cell & Developmental Biology

Key Properties

• CAS Number: 700874-71-1
• MW: 441.52
• Purity: 99.64%
• Formula: C₂₆H₂₇N₅O₂
• SMILES: C(CN1CCOCC1)Oc1ccc2c(ccnc2c1)-c1c2CCCn2nc1-c1ccccn1
• Target: Autophagy,TGF-beta/Smad
• Solubility: Ethanol:Insoluble;H2O:Insoluble;10% DMSO+40% PEG300+5% Tween 80+45% Saline:1 mg/mL (2.26 mM);DMSO:6.88 mg/mL (15.58 mM)

Bioactivity

• Target IC50:
  TβRI:38 nM (Ki, cell free)|TβRII:300 nM (Ki, cell free)
• In Vivo:
  LY2109761 (50 mg/kg, p.o.) greatly reduce the tumor volume and increase the median survival duration o the mice to 45.0 days, bu the differences were not significant. Only when LY2109761 was combined with gemcitabine were significant effects noted on tumor volume (P < 0.05) and median survival duration, which was increased to 77.5 days (P = 0.0018). In an orthotopic intracranial model, LY2109761 significantly reduced tumor growth, prolonged survival, and extende the prolongation of survival induced by radiation treatment. Histologic Analyses showed that LY2109761 inhibited tumor invasion promoted by radiation, reduced tumor microvessel density, and attenuated mesenchymal transition.
• In Vitro:
  Targeting TβRI/II kinase activity with LY2109761 (5 μM) almost completely suppressed bot the basal (P = 0.0107) and TGF-β1–stimulated migration of L3.6pl/GLT cells (P < 0.0001), indicating tha the migration of L3.6pl/GLT cells in vitro is effectively driven by endogenous TGF-β. LY2109761 (0.001-0.1 μM) up-regulates (p < 0.001) E-cadherin mRNA and protein levels. This increase was localized a the cellular membrane where E-cadherin mediates anchorage that is cell-cell dependent. LY2109761 (10 μM) or radiation (4 Gy) alone reduced neurosphere-forming efficiency in nMA-23 cells the combination of LY2109761 plus radiation had supra-additive effects in neurosphere formation and limiting dilution assays.
• Cell Research:
  LY2109761 cytotoxicity was determined by 3 methods the MTT assay, manual counting of viable cells, and propidium iodide staining. MTT yields a purple formazan product that is detected using a 96-well plate reader at 570 nM. Cells were plated and cultured for 2 days in a 1% fetal bovine serum medium supplemented with LY2109761 a the following concentration : 0.001, 0.01, 0.1, 1, 10, and 20 μM. Each Experimental condition was reproduced in 8 wells, and Each experiment was repeated 3 times. To confir the cytotoxic data, cells were incubated unde the described conditions and stained wit the vital dye trypan blue, which does not react wit the cell membrane because of its negative charge. Al the unstained cells were counted using a hemocytometer. Four squares were counted for Each condition, and Each condition was repeated in triplicate in the same experiment. Each experiment was repeated 3 times for Each cell line. Bars represen the average and s andard deviation of All experiments. Unde the same Experimental conditions, nonpermeabilized cells were stained with propidium iodide and analyzed with a flow cytometer.
• Animal Research:
  Three days afte the orthotopic implantation of 1.0 × 106 L3.6pl/GLT tumor cells in 50 μL of HBSS, when bioluminescence imaging confirmed that tumors were well established, 40 mice were andomly allocated into four groups (n = 10 mice per group) to receive one o the following treatments. (a) Vehicle solution for 50 μL of LY2109761 twice a day p.o. (days 1–5 of Each week) and 50 μL of sterile saline daily i.p. (days 2 and 5 of Each week; control group). (b) LY2109761 (50 mg/kg) twice a day p.o. (days 1–5 of Each week) and 50 μL of sterile saline daily i.p. (days 2 and 5 of Each week). (c) Gemcitabine (25 mg/kg) daily i.p. (days 2 and 5 of Each week) and p.o. Vehicle for 50μL of LY2109761 twice a day (days 1–5 of Each week). (d) LY2109761 (50 mg/kg) twice a day (days 1–5 of Each week) and gemcitabine (25 mg/kg) daily i.p. (days 2 and 5 of Each week). Treatments were continued for 4 wk. All mice were weighed weekly and observed for tumor growth. Tumor diameter was assessed with a Vernier caliper, and tumor volume (mm3) was calculated as d2 × D/2, wherein d and D represen the shortest and longest diameters, respectively Bulky disease was considered present whe the tumor burden was prominent in the mouse abdomen (tumor volume, ≥2,000 mm3). When at least 6 of 10 mice in a treatment group presented with bulky disease the median survival duration for that group was considered to be reached. A the median survival duration o the control group the tumor growth in mice in All groups was evaluated usin the bioluminescence emitted b the tumor cells. Bioluminescence imaging was conducted using a cryogenically cooled IVIS 100 imaging system coupled to a data Acquisition computer running Living Image software the mice were sacrificed by carbon dioxide inhalation when evidence of advanced bulky disease was present the day of sacrifice was considere the day of death for survival evaluation.

Storage & Handling

• Storage: store at low temperature | Powder: -20°C for 3 years | In solvent: -80°C for 1 year | Shipping with blue ice/Shipping at ambient temperature.
• Disclaimer: For research use only

Alternative Names

Smad, TβRI, TβRII, Transforming growth factor beta receptors, TGF-β/Smad, TGF-β Receptor, TGFβ, TGF-beta, TGFbeta/Smad, TGFbeta, TGFb, TGF-b/Smad, Autophagy, Inhibitor, inhibit, LY2109761, LY-2109761, LY 2109761

Compound Identifiers

PubChem CID

11655119