The TGF-β pathway regulates a wide variety of cellular processes in many different cell types and biological contexts. There are three identified TGF receptor ligands, TGF-β1, 2, and 3. Activated TGF-β ligands can interact with TGF-β type II receptors (TβRII), then recruit and phosphorylate the TGF-β type I receptors (also called as TβRI or ALK5). In turn, activated TβRI phosphorylates SMAD2 and SMAD3 at C-terminal serine residues. Following that, phosphorylated SMAD and SMAD3 assemble into heterodimeric and trimeric complexes with SMAD4. Then the trimeric complex translocates into the nucleus and regulates the expression of TGF-β target genes[2]. LY2109761 is a dual inhibitor of TGF-βRI and TGF-βRII with Ki values of 38 and 300nM (measured by in vitro kinase assay). Pre-treatment with LY2109761 of 5uM concentration for 24h (serum free) can abolish the p-smad2 induced by TGF-β receptor which activated by TGF-β/serum in the following 30min in L3.6pl/GLT cells. Inhibition of TGF-βRI/II pathway with LY2109761 (5uM) significantly enhanced the anoikis in L3.6pl/GLT cells for 8h. LY2109761 of 5uM for 48-hour treatment can abolish the TGF-β1–stimulated migration and invasiveness of L3.6pl/GLT cells, the metastatic variant of pancreatic cancer cells. 50mg/kg of LY2109761 orally given to mice twice a day, 5 days per week for 4 weeks, shows antimetastatic effect in pancreatic cancer cell spontaneous metastasis models[1]. The invasiveness of the embryonic chicken vasculature by HLE tumors were decreased with treatment of 0.1uM LY2109761 for 48h, showing that LY2109761 can inhibit HLE tumors invading stroma and blood vessels[3].
作用机制
LY2109761 binds to the ATP binding site of the TGF-β R1 kinase domain. [4]
LY2109761 细胞实验
Cell Line
Concentration
Treated Time
Description
References
Esophageal squamous cell carcinoma cells
20 μM
24 h
LY2109761 reduced DJ-1-induced metastasis of bystander ESCC cells
J Exp Clin Cancer Res. 2022 Aug 26;41(1):259.
U251 cells
2 mg/ml
24 h and 48 h
Inhibition of TGFβ pathway, weakening the interaction between RUNX1 and p-SMAD3/SUV39H1
Cell Death Dis. 2019 Nov 21;10(12):877.
N9 cells
2 mg/ml
24 h and 48 h
Inhibition of TGFβ pathway, weakening the interaction between RUNX1 and p-SMAD3/SUV39H1
Cell Death Dis. 2019 Nov 21;10(12):877.
CT26 cells
10 μM
25 h
LY2109761 inhibits TGF-β-mediated cell migration, invasion, and tumorigenicity
Cancer Lett. 2009 May 8;277(1):114-20.
CT26-Luc cells
10 μM
5 days
LY2109761 inhibits TGF-β-mediated cell migration, invasion, and tumorigenicity
Cancer Lett. 2009 May 8;277(1):114-20.
A549 cells
2μM
72 h
To evaluate the effect of LY2109761 on TGF-β or S1P-induced epithelial-mesenchymal transition (EMT). The results showed that LY2109761 reversed the morphological changes induced by TGF-β or S1P, inhibited the up-regulation of the mesenchymal marker CD90 and the down-regulation of the epithelial marker CD326.
Br J Pharmacol. 2022 Apr;179(8):1753-1768.
MC38 cells
5 μM
5 days
LY2109761 inhibited TGF-β-induced proliferation, migration, and invasion of MC38 cells.
Gastroenterology. 2010 Mar;138(3):969-80.e1-3.
SW620 cells
5 μM
5 days
LY2109761 inhibited TGF-β-induced migration and invasion of SW620 cells.
Gastroenterology. 2010 Mar;138(3):969-80.e1-3.
PANC-1 cells
5 μM
72 h
To evaluate the cytotoxicity of LY2109761 on PANC-1 cells, results showed that LY2109761 did not exhibit significant cytotoxicity at low concentrations, with only minor toxicity observed at 50 μM.
ACS Appl Mater Interfaces. 2019 Dec 11;11(49):45390-45403.
Pancreatic stellate cells (PSCs)
5 μM
48 h
To evaluate the inhibitory effect of LY2109761 on type I collagen expression in pancreatic stellate cells (PSCs), results showed that LY2109761 significantly reduced type I collagen expression.
ACS Appl Mater Interfaces. 2019 Dec 11;11(49):45390-45403.
LY2109761 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Nude mice
Pulmonary metastasis model
Intraperitoneal injection
50 mg/kg
Once a week for 6 weeks
LY2109761 significantly suppressed the invasion of K150 cells and alleviated pulmonary metastasis
J Exp Clin Cancer Res. 2022 Aug 26;41(1):259.
Mice
PVR mouse model
Intraperitoneal injection
10 mg/kg
Consecutive 14 days
To investigate the inhibitory effect of LY2109761 on fibrosis induced by FXa in PVR mouse model, results showed LY2109761 significantly alleviated FXa-induced fibrosis.
Invest Ophthalmol Vis Sci. 2021 Jul 1;62(9):29
Nude mice
Patient-derived xenograft (PDX) model
Tail vein injection
50 mg/kg
Once every other day for 15 days
Inhibition of TGFβ pathway, reducing tumor growth and invasion
Cell Death Dis. 2019 Nov 21;10(12):877.
Balb/c mice
Balb/c nude mice
Oral
50 mg/kg
Twice daily for 23 days
LY2109761 reduces liver metastasis and prolongs survival
Cancer Lett. 2009 May 8;277(1):114-20.
BALB/c mice
Asthma-like disease model
Subcutaneous injection
50 mg/kg
Single dose 15 minutes before
To evaluate the effect of LY2109761 on S1P-induced asthma-like features. The results showed that LY2109761 inhibited S1P-induced airway hyperresponsiveness (AHR), mucus hyperproduction, and pulmonary fibrosis, and reversed S1P-induced CD90 up-regulation and CD326 down-regulation.
Br J Pharmacol. 2022 Apr;179(8):1753-1768.
C57BL/6 mice
Colorectal cancer liver metastasis model
Oral
50 mg/kg
Twice daily for 28 days
LY2109761 significantly inhibited the metastasis of colorectal cancer cells to the liver and prolonged the survival of mice.
Gastroenterology. 2010 Mar;138(3):969-80.e1-3.
Mice
MiR-424(322)/503 double-knockout mice
Oral
50 mg/kg
Twice daily for 24 hours
To inhibit TGF-β signaling and observe its effect on mammary gland involution. Results showed that LY2109761 treatment inhibited involution, maintaining the structure of secretory acini and increasing epithelial density.
Genes Dev. 2014 Apr 1;28(7):765-82
Nude mice
Orthotopic pancreatic cancer model
Intravenous injection
13.2 mg/kg
Every 5 days for a total of 6 injections
To evaluate the antitumor efficacy of LY2109761 in an orthotopic pancreatic cancer model, results showed that LY2109761 significantly inhibited tumor growth and reduced collagen expression and activation of PSCs in the tumor.
ACS Appl Mater Interfaces. 2019 Dec 11;11(49):45390-45403.
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