LY2157299TGF-βR1 inhibitor,potent and selective CAS# 700874-72-2 |
Quality Control & MSDS
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| Cas No. | 700874-72-2 | SDF | Download SDF |
| PubChem ID | 10090485 | Appearance | Powder |
| Formula | C22H19N5O | M.Wt | 369.42 |
| Type of Compound | N/A | Storage | Desiccate at -20°C |
| Synonyms | Galunisertib | ||
| Solubility | DMSO : 100 mg/mL (270.69 mM; Need ultrasonic) H2O : < 0.1 mg/mL (insoluble) | ||
| Chemical Name | 4-[2-(6-methylpyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]quinoline-6-carboxamide | ||
| SMILES | CC1=CC=CC(=N1)C2=NN3CCCC3=C2C4=C5C=C(C=CC5=NC=C4)C(=O)N | ||
| Standard InChIKey | IVRXNBXKWIJUQB-UHFFFAOYSA-N | ||
| Standard InChI | InChI=1S/C22H19N5O/c1-13-4-2-5-18(25-13)21-20(19-6-3-11-27(19)26-21)15-9-10-24-17-8-7-14(22(23)28)12-16(15)17/h2,4-5,7-10,12H,3,6,11H2,1H3,(H2,23,28) | ||
| General tips | For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months. We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months. Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it. |
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| About Packaging | 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial. 2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial. 3. Try to avoid loss or contamination during the experiment. |
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| Shipping Condition | Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request. | ||
| Description | LY2157299 is a potent inhibitor of TGFβ receptor I (TβRI) with IC50 of 56 nM. | |||||
| Targets | TβRI | |||||
| IC50 | 56 nM | |||||
| Cell experiment: [1] | |
| Cell lines | HLE and HLF cells |
| 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. |
| Reacting condition | 100 nM, 16 hours |
| Applications | HLE and HLF cells were allowed to migrate for 16 hours on fibronectin, vitronectin, laminin-5 and fibrinogen in the presence of increasing concentrations (1 nM, 10 nM and 100 nM) of LY2157299. LY2157299 significantly inhibited HLE and HLF migration on different ECM substrates. When testing the inhibition of Smad phosphorylation, two different HCC cell lines were pretreated for 16 hours with 100 nM of LY2157299 and then stimulated with 2 ng of TGF-β1 for 30 min. LY2157299 inhibited de novo phosphorylation of p-SMAD2 at the same efficiency in HLE and HLF after stimulation with TGF-β1. Besides that, increased expression of E-cadherin was observed in HLE and HLF cells after treatment for 48 hours. |
| Animal experiment: [2] | |
| Animal models | Nude mice implanted with Calu6 or MX1 cells |
| Dosage form | Oral administration, 75mg/kg, twice a day |
| Application | LY2157299 induced a 70% decrease in phosphorylated Smad (pSmad) for both types of cell lines. The time at which pSmad recovered 80% of baseline was approximately 6 h after administration. |
| 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. |
| References: [1] Dituri F, Mazzocca A, Peidrò F J, et al. Differential inhibition of the TGF-β signaling pathway in HCC cells using the small molecule inhibitor LY2157299 and the D10 monoclonal antibody against TGF-β receptor type II. PloS one, 2013, 8(6): e67109. [2] Bueno L, de Alwis D P, Pitou C, et al. Semi-mechanistic modelling of the tumour growth inhibitory effects of LY2157299, a new type I receptor TGF-β kinase antagonist, in mice. European journal of cancer, 2008, 44(1): 142-150. | |
LY2157299 Dilution Calculator
LY2157299 Molarity Calculator
| 1 mg | 5 mg | 10 mg | 20 mg | 25 mg | |
| 1 mM | 2.7069 mL | 13.5347 mL | 27.0695 mL | 54.1389 mL | 67.6737 mL |
| 5 mM | 0.5414 mL | 2.7069 mL | 5.4139 mL | 10.8278 mL | 13.5347 mL |
| 10 mM | 0.2707 mL | 1.3535 mL | 2.7069 mL | 5.4139 mL | 6.7674 mL |
| 50 mM | 0.0541 mL | 0.2707 mL | 0.5414 mL | 1.0828 mL | 1.3535 mL |
| 100 mM | 0.0271 mL | 0.1353 mL | 0.2707 mL | 0.5414 mL | 0.6767 mL |
| * Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations. | |||||
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LY2157299 is a potent small-molecule antagonist that specifically inhibits Transforming Growth Factor-β receptor I (TβRI). LY2157299 is now under phase II clinical evaluation of its anti-carcinoma activity against hepatocellular carcinoma and glioblastoma1.
LY2157299 has been shown to inhibit β1-integrin activation and block the invasion and migration of hepatocellular cancer cells. In addition, multiple studies have revealed LY2157299 blocked the CTGF production and inhibited neoangiogenesis resulting suppression of hepatocellular carcinoma growth1.
LY2157299 has been reported to decrease phosphorylated Smad2 and Smad3 expression and inhibit the tumor growth in both human anaplastic carcinoma lung cell (Calu6) or human carcinoma breast cell (MX1) xenografted nude mice2.
References:
1. Giannelli G1, Villa E, Lahn M.Transforming Growth Factor-β as a Therapeutic Target in Hepatocellular Carcinoma. Cancer Res. 2014 Apr 1;74(7):1890-4. doi: 10.1158/0008-5472.CAN-14-0243. Epub 2014 Mar 17.
2. Bueno L1, de Alwis DP, Pitou C, Yingling J, Lahn M, Glatt S, Trocóniz IFSemi-mechanistic modelling of the tumour growth inhibitory effects of LY2157299, a new type I receptor TGF-beta kinase antagonist, in mice. Eur J Cancer. 2008 Jan;44(1):142-50.
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Galunisertib (LY2157299), a transforming growth factor-beta receptor I kinase inhibitor, attenuates acute pancreatitis in rats.[Pubmed:27509307]
Braz J Med Biol Res. 2016 Aug 8;49(9):e5388.
Galunisertib (LY2157299), a selective ATP-mimetic inhibitor of TGF-beta receptor I (TGF-betaRI), is the only known TGF-beta pathway inhibitor. In the present study, we investigated the effect of galunisertib on taurocholate (TAC)-induced acute pancreatitis (AP) in rats, and the role of TGF-beta and NF-kappaB signaling pathways. AP was induced by infusion of TAC into the pancreatic duct of Sprague-Dawley male rats (n=30). The rats (220+/-50 g) were administered galunisertib intragastrically [75 mg.kg-1.day-1 for 2 days (0 and 24 h)]. Serum IL-1beta, IL-6, TNF-alpha, amylase (AMY), lipase (LIP), and myeloperoxidase (MPO) levels were measured by ELISA. NF-kappaB activity was detected by electrophoretic mobility shift assay (EMSA); NF-kappaBp65 and TGF-beta1 proteins, as well as TGF-betaRI and p-Smad2/3 proteins, were detected by western blot assay. Cell apoptosis was detected by TUNEL assay. H&E staining was used to evaluate the histopathological alterations of the pancreas. Galunisertib treatment attenuated the severity of AP and decreased the pancreatic histological score. In addition, number of apoptotic cells were significantly increased in the galunisertib-treated group (16.38+/-2.26) than in the AP group (8.14+/-1.27) and sham-operated group (1.82+/-0.73; P<0.05 and P<0.01, respectively). Galunisertib decreased the expression levels of TGF-betaRI and p-Smad2/3 and inhibited NF-kappaB activation and p65 translocation compared with the sham-operated group. Furthermore, serum IL-1beta, IL-6, TNF-alpha, AMY and LIP levels and tissue MPO activity were significantly decreased in the galunisertib-treated group. Our data demonstrate that galunisertib attenuates the severity of TAC-induced experimental AP in rats by inducing apoptosis in the pancreas, inhibiting the activation of TGF-beta signals and NF-kappaB as well as the secretion of pro-inflammatory cytokines.
TGFbetaR1 Blockade with Galunisertib (LY2157299) Enhances Anti-Neuroblastoma Activity of the Anti-GD2 Antibody Dinutuximab (ch14.18) with Natural Killer Cells.[Pubmed:27756784]
Clin Cancer Res. 2017 Feb 1;23(3):804-813.
PURPOSE: Immunotherapy of high-risk neuroblastoma using the anti-GD2 antibody dinutuximab induces antibody-dependent cell-mediated cytotoxicity (ADCC). Galunisertib, an inhibitor of TGFbetaR1, was examined for its ability to enhance the efficacy of dinutuximab in combination with human ex vivo activated NK (aNK) cells against neuroblastoma. EXPERIMENTAL DESIGN: TGFB1 and TGFBR1 mRNA expression was determined for 249 primary neuroblastoma tumors by microarray analysis. The ability of galunisertib to inhibit SMAD activity induced by neuroblastoma patient blood and bone marrow plasmas in neuroblastoma cells was tested. The impact of galunisertib on TGFbeta1-induced inhibition of aNK cytotoxicity and ADCC in vitro and on anti-neuroblastoma activity in NOD-scid gamma (NSG) mice was determined. RESULTS: Neuroblastomas express TGFB1 and TGFBR1 mRNA. Galunisertib suppressed SMAD activation in neuroblastoma cells induced by exogenous TGFbeta1 or by patient blood and bone marrow plasma, and suppressed SMAD2 phosphorylation in human neuroblastoma cells growing in NSG mice. In NK cells treated in vitro with exogenous TGFbeta1, galunisertib suppressed SMAD2 phosphorylation and restored the expression of DNAM-1, NKp30, and NKG2D cytotoxicity receptors and the TRAIL death ligand, the release of perforin and granzyme A, and the direct cytotoxicity and ADCC of aNK cells against neuroblastoma cells. Addition of galunisertib to adoptive cell therapy with aNK cells plus dinutuximab reduced tumor growth and increased survival of mice injected with two neuroblastoma cell lines or a patient-derived xenograft. CONCLUSIONS: Galunisertib suppresses activation of SMAD2 in neuroblastomas and aNK cells, restores NK cytotoxic mechanisms, and increases the efficacy of dinutuximab with aNK cells against neuroblastoma tumors. Clin Cancer Res; 23(3); 804-13. (c)2016 AACRSee related commentary by Zenarruzabeitia et al., p. 615.
Clinical development of galunisertib (LY2157299 monohydrate), a small molecule inhibitor of transforming growth factor-beta signaling pathway.[Pubmed:26309397]
Drug Des Devel Ther. 2015 Aug 10;9:4479-99.
Transforming growth factor-beta (TGF-beta) signaling regulates a wide range of biological processes. TGF-beta plays an important role in tumorigenesis and contributes to the hallmarks of cancer, including tumor proliferation, invasion and metastasis, inflammation, angiogenesis, and escape of immune surveillance. There are several pharmacological approaches to block TGF-beta signaling, such as monoclonal antibodies, vaccines, antisense oligonucleotides, and small molecule inhibitors. Galunisertib (LY2157299 monohydrate) is an oral small molecule inhibitor of the TGF-beta receptor I kinase that specifically downregulates the phosphorylation of SMAD2, abrogating activation of the canonical pathway. Furthermore, galunisertib has antitumor activity in tumor-bearing animal models such as breast, colon, lung cancers, and hepatocellular carcinoma. Continuous long-term exposure to galunisertib caused cardiac toxicities in animals requiring adoption of a pharmacokinetic/pharmacodynamic-based dosing strategy to allow further development. The use of such a pharmacokinetic/pharmacodynamic model defined a therapeutic window with an appropriate safety profile that enabled the clinical investigation of galunisertib. These efforts resulted in an intermittent dosing regimen (14 days on/14 days off, on a 28-day cycle) of galunisertib for all ongoing trials. Galunisertib is being investigated either as monotherapy or in combination with standard antitumor regimens (including nivolumab) in patients with cancer with high unmet medical needs such as glioblastoma, pancreatic cancer, and hepatocellular carcinoma. The present review summarizes the past and current experiences with different pharmacological treatments that enabled galunisertib to be investigated in patients.
Brain perfusion and permeability in patients with advanced, refractory glioblastoma treated with lomustine and the transforming growth factor-beta receptor I kinase inhibitor LY2157299 monohydrate.[Pubmed:26137087]
Oncol Lett. 2015 Jun;9(6):2442-2448.
Transforming growth factor-beta (TGF-beta) signaling is associated with tumor progression and vascularization in malignant glioma. In the present study, magnetic resonance imaging was used to evaluate changes in the size and vascularity of glioblastomas in 12 patients who were treated with lomustine and the novel inhibitor of TGF-beta signaling, LY2157299 monohydrate. A response in tumor size was observed in 2 of the 12 patients; in 1 of these 2 patients, a reduction in vascular permeability and perfusion was also detected. The effect was observed following 4 cycles of treatment (~3 months). Changes in vascularity have not previously been attributed to treatment with lomustine; therefore, the effect may be associated with LY2157299 treatment. LY2157299 does not appear to have an anti-angiogenic effect when combined with lomustine, and hence may have a different mechanism of action profile compared with anti-angiogenic drugs.
