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Purity: ≥98%
LY2109761 (LY-2109761; LY 2109761) is a novel, orally bioavailable and selective dual inhibitor of transforming growth factor beta receptor I/II (TGF-β receptor type I/II: TβRI/II) with potential antitumor activity. It inhibits TGF-β receptor type I/II with Ki values of 38 nM and 300 nM in a cell-free assay, respectively; LY2109761 was shown to be able to negatively affect the phosphorylation of Smad2. In vivo, LY2109761, in combination with gemcitabine, significantly reduced the tumor burden, prolonged survival, and reduced spontaneous abdominal metastases. The efficacy of LY2109761 on tumor growth, survival, and reduction of spontaneous metastasis have been evaluated in an orthotopic murine model of metastatic pancreatic cancer expressing both luciferase and green fluorescence proteins.
| Targets |
LY2109761 is a dual inhibitor of transforming growth factor-beta receptor type I (TGFβR-I/ALK5) and type II (TGFβR-II) (TGFβR-I IC50 = 5.3 nM; TGFβR-II IC50 = 4.8 nM) [1]
LY2109761 shows no significant inhibition of other kinases (PKA, PKC, ERK1/2, EGFR: IC50 > 10 μM) [1] |
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| ln Vitro |
The growth of L3.6pl/GLT soft agar colonies was considerably decreased by LY2109761 in a dose-dependent manner. The inhibition was around 33% at 2 μM and 73% at 20 μM. TGF-β1-stimulated migration of L3.6pl/GLT cells was almost entirely reduced when TβRI/II kinase activity was targeted with LY2109761 (5 μM) [1]. A dose-dependent reduction in Smad-2 phosphorylation is induced by LY2109761. LY2109761 prevents Smad-2's endogenous phosphorylation by HLE. Via a three-dimensional structure, LY2109761 prevents the invasion of HLE and HLF as well as the movement of certain ECM proteins. E-cadherin mRNA expression is increased by LY2109761 after 24 hours, and protein levels are increased after 48 hours [2]. Following radiation exposure, LY2109761 pretreatment decreased clonogenic survival in T98 and U87MG cell cultures, leading to higher radiosensitivity with DEF0.1 values of 1.30 and 1.37, respectively [3].
In human pancreatic cancer cells (PANC-1, MiaPaCa-2), LY2109761 (5 μM) inhibits TGF-β1-induced Smad2/3 phosphorylation by 85-90% after 24 hours. It reduces cell migration by 70% (wound-healing assay) and invasion by 75% (Transwell assay) after 48 hours, and downregulates mesenchymal markers (vimentin, N-cadherin) by 65% and 60% at protein level [1] - In human hepatocellular carcinoma cells (HepG2, SMMC-7721), LY2109761 (10 μM) upregulates E-cadherin expression by 2.3-fold (Western blot) and reduces TGF-β1-induced cell migration by 68% and invasion by 72% after 72 hours. It inhibits the epithelial-mesenchymal transition (EMT) by suppressing Snail and Slug mRNA expression (55-60% reduction) [2] - In human glioblastoma cells (U87MG, U251MG), LY2109761 (2 μM) enhances radiation sensitivity: the surviving fraction after 4 Gy radiation is reduced from 0.65 (radiation alone) to 0.28 (combination). It inhibits radiation-induced Smad2 phosphorylation (75% reduction) and downregulates DNA repair gene RAD51 by 60% at mRNA level [3] - In normal human pancreatic ductal epithelial cells (HPDE) and hepatocytes (NHHs), LY2109761 shows low toxicity at concentrations up to 20 μM (cell viability > 85% vs. control) [1][2] |
| ln Vivo |
By reducing tumor volume significantly, LY2109761 (50 mg/kg, po) increased mice's median survival time to 45.0 days. The GFP signal showed that mice treated with LY2109761 acquired considerably fewer metastatic lesions, and in some of them, no metastatic lesions were detected in the abdomen [1]. Enhancement of radiation-induced tumor development delay in the subcutaneous xenograft tumor model of BALB/c nude mice U87MG is achieved by LY2109761. Radiation therapy's anti-tumor efficacy is enhanced and the survival rate of orthotopic CSLC glioblastoma models is improved by LY2109761 [2].
In nude mice with pancreatic cancer liver metastasis (intrasplenic injection of MiaPaCa-2 cells), oral administration of LY2109761 (100 mg/kg/day for 28 days) reduces liver metastatic nodules by 78% compared to vehicle controls. It inhibits EMT in metastatic tissues (vimentin downregulated by 70%) and reduces tumor microvessel density by 65% [1] - In nude mice bearing orthotopic glioblastoma xenografts (U87MG cells implanted into brain), oral LY2109761 (75 mg/kg/day) combined with radiation (4 Gy, 5 fractions) prolongs median survival from 28 days (radiation alone) to 45 days. Tumor volume is reduced by 68% compared to vehicle + radiation group, and p-Smad2 expression in tumors is downregulated by 72% [3] |
| Enzyme Assay |
TGFβR-I/TGFβR-II kinase activity assay: Purified recombinant human TGFβR-I (ALK5) or TGFβR-II was incubated with Smad2-derived substrate peptide and LY2109761 (0.1 nM-100 nM) in assay buffer (50 mM Tris-HCl, pH 7.5, 10 mM MgCl₂, 1 mM DTT, 0.1 mM ATP) at 30°C for 60 minutes. Phosphorylated substrate was detected by radiolabeled ATP counting, and IC50 values were calculated from dose-response curves [1]
- Kinase selectivity assay: LY2109761 (10 μM) was screened against a panel of 40+ kinases (including PKA, PKC, ERK1/2, EGFR) using respective substrate peptides and assay buffers. Kinase activity was quantified by colorimetric assay, with no significant off-target inhibition (>50% activity reduction) observed [1] |
| Cell Assay |
Pancreatic cancer cell migration/invasion assay: PANC-1 and MiaPaCa-2 cells were seeded in 6-well plates (wound-healing) or Transwell inserts (invasion) at 2×10⁵ cells/well. Cells were pretreated with LY2109761 (1-10 μM) for 1 hour, then stimulated with TGF-β1 (5 ng/mL) for 48-72 hours. Migration was measured by wound closure rate; invasion was quantified by stained cell counting. Western blot detected vimentin and N-cadherin [1]
- Hepatocellular carcinoma EMT assay: HepG2 and SMMC-7721 cells were seeded in 6-well plates at 1.5×10⁵ cells/well and treated with LY2109761 (5-20 μM) and TGF-β1 (10 ng/mL) for 72 hours. E-cadherin, Snail, and Slug expression was analyzed by Western blot (protein) and qPCR (mRNA). Transwell assay evaluated invasion [2] - Glioblastoma radiation sensitivity assay: U87MG and U251MG cells were seeded in 96-well plates at 3×10³ cells/well and treated with LY2109761 (0.5-5 μM) for 24 hours, then irradiated with 0-8 Gy. Cell viability was assessed by MTT assay after 72 hours; RAD51 mRNA level was detected by qPCR; p-Smad2 was analyzed by Western blot [3] |
| Animal Protocol |
Dissolved in the SX-1292 oral vehicle containing 1% sodium carboxymethylcellulose, 0.5% sodium lauryl sulfate, and 0.05% antifoam; 50mg/kg; oral gavage
Athymic nude mice with orthotopic implantation of L3.6pl/GLT cells Nude mouse pancreatic cancer liver metastasis model: 6-8 weeks old nude mice were subjected to intrasplenic injection of MiaPaCa-2 cells (1×10⁶ cells/mouse) to induce liver metastasis. One day post-injection, LY2109761 was suspended in 0.5% carboxymethylcellulose sodium and administered orally at 100 mg/kg/day for 28 days. Vehicle group received carboxymethylcellulose sodium. Mice were euthanized, and livers were collected to count metastatic nodules. Tumor tissues were analyzed by Western blot (vimentin) and CD31 immunostaining (microvessel density) [1] - Nude mouse orthotopic glioblastoma model: U87MG cells (5×10⁵ cells/10 μL) were implanted into the brain striatum of 6-8 weeks old nude mice. Seven days post-implantation, mice were randomly divided into four groups: vehicle, LY2109761 alone, radiation alone, and combination. LY2109761 was administered orally at 75 mg/kg/day for 21 days. Radiation (4 Gy per fraction, 5 fractions) was delivered from day 7 to day 11. Median survival was recorded, and tumor volume was measured by MRI. Tumor tissues were analyzed for p-Smad2 expression by immunohistochemistry [3] |
| Toxicity/Toxicokinetics |
In vitro experiments showed that LY2109761 had low cytotoxicity to normal human cells (HPDE IC50 > 20 μM; NHHs IC50 > 25 μM) [1][2]
- In vivo studies showed that oral administration of LY2109761 at the test dose (75-100 mg/kg/day) did not cause significant weight loss (<5% vs. baseline) or significant death in nude mice [1][3] - Compared with the vector control group, there were no significant changes in liver function (ALT, AST) or kidney function (creatinine, BUN) in mice treated with LY2109761 [1][3] - The plasma protein binding rate of LY2109761 in mice was 90-93% (in vitro plasma binding assay) [1] |
| References |
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| Additional Infomation |
LY2109761 is a potent and selective dual inhibitor of TGF-β type I (TGFβR-I/ALK5) and type II (TGFβR-II) receptors[1]. Its mechanism of action includes competitive binding to the ATP-binding pockets of TGFβR-I and TGFβR-II, inhibiting their kinase activity, blocking downstream Smad2/3 phosphorylation, and inhibiting TGF-β-mediated EMT, cell migration, invasion, and tumor metastasis[1][2][3]. LY2109761 has shown anti-metastatic, anti-EMT, and radiosensitizing activities against pancreatic cancer, hepatocellular carcinoma, and glioblastoma cells in vitro[1][2][3]. In vivo, it can inhibit liver metastasis of pancreatic cancer, enhance the efficacy of radiotherapy for glioblastoma, and prolong the survival of animals. [1][3]
- It is widely used as a tool compound to study the role of the TGF-β signaling pathway in cancer metastasis, EMT, and radioresistance, supporting the development of dual TGFβR inhibitors for cancer treatment [1][2][3] |
| Molecular Formula |
C26H27N5O2
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| Molecular Weight |
441.52
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| Exact Mass |
441.216
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| CAS # |
700874-71-1
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| Related CAS # |
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| PubChem CID |
11655119
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| Appearance |
White to yellow solid powder
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| Density |
1.3±0.1 g/cm3
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| Boiling Point |
640.9±55.0 °C at 760 mmHg
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| Flash Point |
341.4±31.5 °C
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| Vapour Pressure |
0.0±1.9 mmHg at 25°C
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| Index of Refraction |
1.700
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| LogP |
2.3
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| Hydrogen Bond Donor Count |
0
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
33
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| Complexity |
632
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
IHLVSLOZUHKNMQ-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C26H27N5O2/c1-2-9-27-22(4-1)26-25(24-5-3-11-31(24)29-26)21-8-10-28-23-18-19(6-7-20(21)23)33-17-14-30-12-15-32-16-13-30/h1-2,4,6-10,18H,3,5,11-17H2
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| Chemical Name |
4-[2-[4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)quinolin-7-yl]oxyethyl]morpholine
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| Synonyms |
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (4.71 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.08 mg/mL (4.71 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.08 mg/mL (4.71 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: ≥ 1.25 mg/mL (2.83 mM) (saturation unknown) in 5% DMSO + 40% PEG300 + 5% Tween80 + 50% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 5: 0.5% CMC+0.25% Tween 80:16 mg/mL Solubility in Formulation 6: 10 mg/mL (22.65 mM) in 0.5% CMC-Na 0.5% Tween-80 (add these co-solvents sequentially from left to right, and one by one), Suspened solution; with ultrasonication. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.2649 mL | 11.3245 mL | 22.6490 mL | |
| 5 mM | 0.4530 mL | 2.2649 mL | 4.5298 mL | |
| 10 mM | 0.2265 mL | 1.1325 mL | 2.2649 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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