LY2109761 |
| Catalog No.GC12363 |
LY2109761 est un inhibiteur sélectif du récepteur TGF-β de type I/II actif par voie orale avec Kis de 38 nM et 300 nM, respectivement.
Products are for research use only. Not for human use. We do not sell to patients.
Cas No.: 700874-71-1
Sample solution is provided at 25 µL, 10mM.
LY2109761 is a small-molecule inhibitor selectively targeting both TGF-β receptor type I and II ((TβRI/II)) with Ki of 38 nM and 300 nM, respectively [1]. It gave IC50 value of 69 nM in TβRI enzymatic assay [2]. Crystal structure showed the binding of LY2109761 to the ATP binding site of the TGF-β R1 kinase domain [2]. Weak inhibitory activities were reported for other kinases, including Lck, Sapk2α, MKK6, Fyn, and JNK3 (18–89% inhibition at 20 µM) [2].
LY2109761 has shown potential anti-tumor activity in preclinical studies. Deregulation of TGF-β signaling pathway is correlated with various malignant. LY2109761 suppressed proliferation, migration and invasion, and induced apoptosis of pancreatic cancer cells [1]. When combined with gemcitabine, it inhibited tumor growth and metastasis in a mouse model of metastatic pancreatic cancer [1]. It also inhibited the anti-apoptotic effects of TGF-beta1 in myelo-monocytic leukaemic cells [3]. Results in GBM cell lines and an orthotopic intracranial model indicated that LY2109761 increased radiosensitivity and resulted in prolonged survival in glioblastoma [4]. In addition, LY2109761 reduced radiation-induced pneumonitis and pulmonary fibrosis in a murine model [5].
References:
[1]Melisi D, Ishiyama S, Sclabas GM et al. LY2109761, a novel transforming growth factor beta receptor type I and type II dual inhibitor, as a therapeutic approach to suppressing pancreatic cancer metastasis. Mol Cancer Ther 2008; 7: 829-840.[2]Li HY, McMillen WT, Heap CR et al. Optimization of a dihydropyrrolopyrazole series of transforming growth factor-beta type I receptor kinase domain inhibitors: discovery of an orally bioavailable transforming growth factor-beta receptor type I inhibitor as antitumor agent. J Med Chem 2008; 51: 2302-2306.[3]Xu Y, Tabe Y, Jin L et al. TGF-beta receptor kinase inhibitor LY2109761 reverses the anti-apoptotic effects of TGF-beta1 in myelo-monocytic leukaemic cells co-cultured with stromal cells. Br J Haematol 2008; 142: 192-201.[4]Zhang M, Kleber S, Rohrich M et al. Blockade of TGF-beta signaling by the TGFbetaR-I kinase inhibitor LY2109761 enhances radiation response and prolongs survival in glioblastoma. Cancer Res 2011; 71: 7155-7167.[5]Flechsig P, Dadrich M, Bickelhaupt S et al. LY2109761 attenuates radiation-induced pulmonary murine fibrosis via reversal of TGF-beta and BMP-associated proinflammatory and proangiogenic signals. Clin Cancer Res 2012; 18: 3616-3627.
| Cell experiment [1]: | |
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Cell lines |
Human cell MDA PCa 2b, PC-3 lines. |
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Preparation method |
The solubility of this compound in DMSO is <10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37 °C for 10 minutes and/or shake it in the ultrasonic bath for a while.Stock solution can be stored below -20°C for several months.. |
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Reacting condition |
24h; 4 μM |
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Applications |
A crucial step in the transduction of TGF-β 1 signals is the phosphorylation of receptor-activated Smad2 and Smad3. We thus assessed the phosphorylation of Smad2 in lysates of MDA PCa 2b cells, PC-3 cells, and PMOs treated with rhTGF- β1. We found that TGF-β1 induces phosphorylation of Smad2 in PC-3 cells and PMOs but not in MDA PCa 2b cells. Further, treatment with LY2109761 reverses the Smad2 phosphorylation induced by rhTGF-β1. In other words, LY2109761 inhibits TGF-β1–induced Smad2 activation in PC-3 cells and PMOs. |
| Animal experiment [1]: | |
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Animal models |
Male SCID mice |
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Dosage form |
200 mg/kg/day; oral taken |
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Application |
After 3 weeks of treatment, X-ray analysis of the vehicle control group revealed two broken bones and loss of 30%–70% of the radiopaque areas in the tumor-bearing bones. MRI analysis showed a significantly smaller tumor volume in the treated group than in the controls (p =0.012). Micro-CT analysis of the tumor-bearing bones of the controls and treated mice demonstrated significantly lower BV (p=0.00043), BMC (p =0.000132), and BMD (p = 0.000085) in the control mice. Furthermore, BV, BMC, and BMD in the treated group were restored to values found in the normal (uninjected) femurs, which supports the efficacy of treatment. Finally, bone histomorphometric analysis demonstrated that LY2109761 inhibited PC-3-induced activation of osteoclasts. |
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Other notes |
Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal. |
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References: [1] Wan X, Li Z G, Yingling J M, et al. Effect of transforming growth factor beta (TGF-β) receptor I kinase inhibitor on prostate cancer bone growth[J]. Bone, 2012, 50(3): 695-703. | |
| Cas No. | 700874-71-1 | SDF | |
| 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 | ||
| Canonical SMILES | C1CC2=C(C(=NN2C1)C3=CC=CC=N3)C4=C5C=CC(=CC5=NC=C4)OCCN6CCOCC6 | ||
| Formula | C26H27N5O2 | M.Wt | 441.52 |
| Solubility | ≥ 22.1mg/mL in DMSO | Storage | Store at -20°C |
| General tips | Please select the appropriate solvent to prepare the stock solution according to the
solubility of the product in different solvents; once the solution is prepared, please store it in
separate packages to avoid product failure caused by repeated freezing and thawing.Storage method
and period of the stock solution: When stored at -80°C, please use it within 6 months; when stored
at -20°C, please use it within 1 month. To increase solubility, heat the tube to 37°C and then oscillate in an ultrasonic bath for some time. |
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| Shipping Condition | Evaluation sample solution: shipped with blue ice. All other sizes available: with RT, or with Blue Ice upon request. | ||
| Prepare stock solution | |||
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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 |
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μL
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Working concentration: mg/ml;
Method for preparing DMSO master liquid: mg drug pre-dissolved in μL DMSO ( Master liquid 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 master liquid, next addμL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O, mix and clarify.
Method for preparing in vivo formulation: Take μL DMSO master liquid, next add μL Corn oil, mix and clarify.
Note: 1. Please make sure the liquid is clear before adding the next solvent.
2. Be sure to add the solvent(s) in order. You must ensure that the solution obtained, in the previous addition, is a clear solution before proceeding to add the next solvent. Physical methods such as vortex, ultrasound or hot water bath can be used to aid dissolving.
3. All of the above co-solvents are available for purchase on the GlpBio website.
Quality Control & SDS
- View current batch:
- Purity: >99.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Average Rating: 5 (Based on Reviews and 36 reference(s) in Google Scholar.)
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