LY2109761

Catalog No.S2704

LY2109761 is a novel selective TGF-β receptor type I/II (TβRI/II) dual inhibitor with Ki of 38 nM and 300 nM in a cell-free assay, respectively; shown to negatively affect the phosphorylation of Smad2.

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LY2109761 Chemical Structure

LY2109761 Chemical Structure
Molecular Weight: 441.52

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Product Description

Biological Activity

Description LY2109761 is a novel selective TGF-β receptor type I/II (TβRI/II) dual inhibitor with Ki of 38 nM and 300 nM in a cell-free assay, respectively; shown to negatively affect the phosphorylation of Smad2.
Targets TβRI [1]
(Cell-free assay)
TβRII [1]
(Cell-free assay)
IC50 38 nM(Ki) 300 nM(Ki)
In vitro LY2109761 treatment induces a dose-dependent low-anchorage growth inhibition of L3.6pl/GLT cells, leading to ~33% or 73% inhibition at 2 μM and 20 μM, respectively, which can be strongly enhanced when combined with gemcitabine in combination index value of 0.36581. Blocking TβRI/II kinase activity with LY2109761 (5 μM) completely suppresses both the basal and TGF-β1-stimulated migration and invasion of L3.6pl/GLT cells, significantly enhances the detachment-induced apoptosis by 26% at 8 hours treatment, and completely suppresses TGF-β–induced Smad2 phosphorylation. [1] LY2109761 treatment at 1 nM is sufficient to significantly block the migration and invasion but not adhesion of hepatocellular carcinoma cells by increasing E-cadherin expression. [2] LY2109761 pretreatment enhances radiosensitivity of glioblastoma cells via TGF-β signaling blockage. LY2109761 (10 μM) reduces the self-renewal and proliferation of GBM-derived cancer stem–like cells (CSLC), which can be significantly enhanced when combined with radiation. [3]
Cell Data
Cell LinesAssay TypeConcentrationIncubation TimeFormulationActivity DescriptionPMID
HepG2 Mkn0SpVv[3Srb36gRZN{[Xl?MlPGNVDDqM7:TdMgNH\vbI8zKGh?NHLyUHFqdmirYnn0d{BifXSxcHjh[5khcW6mdXP0bY9vKGK7IHfhcIFv\2mwMnH5NlUzPjhyNE[=
PC-3Mn\VSpVv[3Srb36gRZN{[Xl?NHPSfG0xNjJxMj:0JO69VQ>?M2PkVlI1KGh?MlniSG1UVw>?NUnJWnpicW6qaXLpeJMhXEeILd8yNgKBm2mwZIXj[YQhW22jZEKgZYN1cX[jdHnvci=>MXOyNlE4OzB3Mx?=
PMOsNUDWW3ZCTnWwY4Tpc44hSXO|YYm=MkDUNE4zNzJxNDFOwG0>MWKyOEBpM1HLVWROW09?NGS4b2xqdmirYnn0d{BVT0ZvzsKx5qCUcW6mdXPl[EBUdWGmMjDhZ5RqfmG2aX;uMVyyNlE4OzB3Mx?=
PC-3MXfHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>?MlTONE4zNzJizszNNF7TbnMzPCCqNYrMXnJSTE2VTx?=NIj5dI1jdG:la4OgeIhmKGmwaHnibZRqd25ib3[gZ4VtdCCycn;sbYZmemG2aX;uJJBzd2S3Y3XkJIJ6KFSJRj5OtlE>Mnq2NlIyPzNyNUO=
PMOsMV;Hdo94fGhiSX7obYJqfGmxbjDBd5NigQ>?MXewMlIwOiEQvF2=MkW1NlQhcA>?MVTEUXNQNU\mTnVK[myxY3vzJJRp\SCrbnjpZol1cW:wIH;mJINmdGxicILvcIln\XKjdHnvckBxem:mdXPl[EBjgSCWR1[t{tIyMnHFNlIyPzNyNUO=
U87MGM1PaR2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7MU[1M|ExKM7:TR?=MWSyJIg>MmG3[Y5p[W6lZYOgdoFlcW:|ZX7zbZRqfmm2eR?=M2ToSVIzODB4OUm4
T98NXeyUXI4T3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm=NHP3VFg2NzFyIN88US=>M1rHblIhcA>?MUDlcohidmOnczDyZYRqd3OnboPpeIl3cXS7NUPFU252OjJyME[5PVg>
U87MGMWPBdI9xfG:|aYOgRZN{[Xl?MXSxNEDPxE1?NETCSXQzKGh?M{fkOoVvcGGwY3XzJJJi\GmjdHnvck1qdmS3Y3XkJGRPSSCmYX3h[4Uh[W6mIHHwc5B1d3OrczDyZZRmew>?MlS5NlIxODZ7OUi=
NMA-23M3zROWFxd3C2b4Ppd{BCe3OjeR?=M4GzSlExKM7:TR?=MknoNkBpNHHteJFmdmijbnPld{Bz[WSrYYTpc44ucW6mdXPl[EBFVkFiZHHtZYdmKGGwZDDhdI9xfG:|aYOgdoF1\XN?MY[yNlAxPjl7OB?=
HLE NGjFVpJHfW6ldHnvckBCe3OjeR?=MmXJNE4xOS1zMEFCpI5OMmf6OFghcA>?NXjr[WxocW6qaXLpeJMhfGinIH3p[5JifGmxbjDpckBiKGSxc3Wt[IVx\W6mZX70JI1idm6nch?=NGPlO|EzODh2NEi3PC=>
HLFMUXGeY5kfGmxbjDBd5NigQ>?NYPIeY0zOC5yMT2xNFDDqG6PNV21UZBZPDhiaB?=MYXpcohq[mm2czD0bIUhdWmpcnH0bY9vKGmwIHGg[I9{\S2mZYDlcoRmdnRibXHucoVzMl7DNlA5PDR6N{i=
10A/HER2YVMAMVrHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>?MnS5NE4yNTBwNTFOwG0>MX:5JIQ>NWfCTYN4emWmdXPld{B1cGVic3n6[UwhcW64YYPpeoVv\XO|IHHu[EBk\WyuIH71cYJmeiCxZjDjc4xwdmmncx?=NWK4Smh{OjB|OEOxPVc>
MC38 NGPHZ4pIem:5dHigTY5pcWKrdHnvckBCe3OjeR?=NIjPPGw2KM7:TR?=NHnNXZc2KGR?M{\PNolvcGmkaYTzJINmdGxiZ4Lve5RpKGmwIHGgeIlu\S2mZYDlcoRmdnRibXHucoVzNIWwSocyQTlyOUe0OC=>
U937NYLNUmU3T3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm=NYHPdXE4PS1{MDFOwG0>MYiyOE04OiCqM37qfolvcGmkaYTzJINmdGxiZ4Lve5RpKHOuaXfoeIx6MkfxNVg1QTJzMUO=
HLE M1r3RmN6fG:2b4jpeJkhSXO|YYm=NVOzXYFOOC5yMEGtNlAh|ryPNYGwXIw1PDhiaB?=M2TWWolv\HWlZYOgZ4VtdCCleYTveI95cXS7IHnuJIEh\G:|ZT3k[ZBmdmSnboSgcYFvdmW{MVyxPFMyQDR2Mx?=
HLFNWLxOpJyS3m2b4TvfIl1gSCDc4PhfS=>Mkn4NE4xODFvMkCg{txONFfwPYk1QCCqMVXpcoR2[2W|IHPlcIwh[3m2b4TvfIl1gSCrbjDhJIRwe2VvZHXw[Y5l\W62IH3hco5meg>?M4O3[lE5OzF6NESz

... Click to View More Cell Line Experimental Data

In vivo Administration of LY2109761 (50 mg/kg) alone or in combination with gemcitabine (25 mg/kg) significantly reduces the tumor volume by ~70% and ~90%, respectively, prolongs the survival with the median survival duration of 45.0 days and 77.5 days, respectively, and reduces spontaneous abdominal metastases in the L3.6pl/GLT Xenograft mice model. [1] In consistent with the in vitro effect, administration of LY2109761 alone or in combination with radiation, markedly inhibits tumor growth in the orthotopical CSLC glioblastoma model by 43.4% and 76.3%, respectively, decreases tumor invasion and tumor microvessel density, and significantly enhances radiation-induced tumor growth delay in the U87MG xenograft mice model. [3]
Features

Protocol(Only for Reference)

Cell Assay: [1]

Cell lines Colo357FG/GLT, and Colo357L3.6pl/GLT
Concentrations Dissolved in DMSO, final concentrations ~10 μM
Incubation Time 48 hours
Method Cells are exposed to increasing doses of LY2109761 (~10 μM) for 48 hours. The medium containing drugs is removed, the cells are washed twice with PBS, and fresh medium is added. After 5 days of incubation, the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay is used to obtain relative variable cell numbers.

Animal Study: [1]

Animal Models Athymic nude mice with orthotopic implantation of L3.6pl/GLT cells
Formulation Dissolved in the SX-1292 oral vehicle containing 1% sodium carboxymethylcellulose, 0.5% sodium lauryl sulfate, and 0.05% antifoam
Dosages 50 mg/kg
Administration Twice a day p.o.

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

SpeciesMouseRatRabbitGuinea pigHamsterDog
Weight (kg)0.020.151.80.40.0810
Body Surface Area (m2)0.0070.0250.150.050.020.5
Km factor36128520
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)
1

References

[1] Melisi D, et al. Mol Cancer Ther, 2008, 7(4), 829-840.

[2] Fransvea E, et al. Hepatology, 2008, 47(5), 1557-1566.

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Chemical Information

Download LY2109761 SDF
Molecular Weight (MW) 441.52
Formula

C26H27N5O2

CAS No. 700874-71-1
Storage 3 years -20℃powder
2 years -80℃in solvent
Synonyms N/A
Solubility (25°C) * In vitro DMSO 2 mg/mL (4.52 mM)
Water <1 mg/mL
Ethanol <1 mg/mL
In vivo 0.5% CMC+0.25% Tween 80 16 mg/mL
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
Chemical Name 7-(2-morpholinoethoxy)-4-(2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)quinoline

Tech Support

Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
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