LY2109761 化学構造
分子量: 441.52

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製品説明

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製品の説明

生物活性

製品説明 LY2109761は、新しい選抜TGFβレセプター・タイプIとタイプII(TβRI/II)二重阻害剤で、 Ki がそれぞれ38 nM と 300 nMになる。
ターゲット TβRI TβRII
IC50 38 nM (Ki) 300 nM (Ki) [1]
In vitro試験 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  MXTGeY5kfGmxbjDBd5NigQ>? MV2xNOKh|ryPwrC= M3X0XFIhcA>? M2rxRolvcGmkaYTzJIF2fG:yaHHnfUBqdmS3Y4Tpc44h[nliZ3HsZY5ocW5? MoLGNlUzPjhyNE[=
PC-3 M3iySGZ2dmO2aX;uJGF{e2G7 NFrjNWMxNjJxMj:0JO69VQ>? MkfqNlQhcA>? MVfEUXNQ MXjpcohq[mm2czDUS2Yu|rJz4pETbY5lfWOnZDDTcYFlOiCjY4TpeoF1cW:w NYDBfZQzOjJzN{OwOVM>
PMOs MYHGeY5kfGmxbjDBd5NigQ>? NYL1[4VJOC5{L{KvOEDPxE1? NGDubowzPCCq MV3EUXNQ Mk\hbY5pcWKrdIOgWGdHNc7{MfMAl4lv\HWlZXSgV41i\DJiYXP0bZZifGmxbh?= Mmm5NlIyPzNyNUO=
PC-3 MXLHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MYWwMlIwOiEQvF2= NFTIO3QzPCCq NXPIV2txTE2VTx?= NEjLS2VjdG:la4OgeIhmKGmwaHnibZRqd25ib3[gZ4VtdCCycn;sbYZmemG2aX;uJJBzd2S3Y3XkJIJ6KFSJRj5OtlE> M1XLdlIzOTd|MEWz
PMOs MlfOS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MWCwMlIwOiEQvF2= M3\HRVI1KGh? MlXpSG1UVw>? NHjWXINjdG:la4OgeIhmKGmwaHnibZRqd25ib3[gZ4VtdCCycn;sbYZmemG2aX;uJJBzd2S3Y3XkJIJ6KFSJRj5OtlE> M3H4[VIzOTd|MEWz
U87MG MWnHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NVjTbJRSPS9zMDFOwG0> MoDjNkBp M4LQRoVvcGGwY3XzJJJi\Gmxc3Xud4l1cX[rdIm= M3jTO|IzODB4OUm4
T98 M{DOdWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NF\IZ4E2NzFyIN88US=> NGHPOWwzKGh? MU\lcohidmOnczDyZYRqd3OnboPpeIl3cXS7 M4P3SlIzODB4OUm4
U87MG NFK3d49CeG:ydH;zbZMhSXO|YYm= MVqxNEDPxE1? NHHCPIIzKGh? MWTlcohidmOnczDyZYRq[XSrb36tbY5lfWOnZDDEUmEh\GGvYXflJIFv\CCjcH;weI9{cXNicnH0[ZM> MlfWNlIxODZ7OUi=
NMA-23 MVPBdI9xfG:|aYOgRZN{[Xl? Mn;nNVAh|ryP Mk\rNkBp MVTlcohidmOnczDyZYRq[XSrb36tbY5lfWOnZDDEUmEh\GGvYXflJIFv\CCjcH;weI9{cXNicnH0[ZM> M4DaW|IzODB4OUm4
HLE  M3;3RmZ2dmO2aX;uJGF{e2G7 NFW5c3MxNjBzLUGwNOKhdk1? M1LTWlQ5KGh? MnnTbY5pcWKrdIOgeIhmKG2rZ4LheIlwdiCrbjDhJIRwe2VvZHXw[Y5l\W62IH3hco5meg>? MmnONlA5PDR6N{i=
HLF MonJSpVv[3Srb36gRZN{[Xl? NFnDOGgxNjBzLUGwNOKhdk1? MVO0PEBp M3f5XYlvcGmkaYTzJJRp\SCvaXfyZZRqd25iaX6gZUBld3OnLXTldIVv\GWwdDDtZY5v\XJ? Mnm1NlA5PDR6N{i=
10A/HER2YVMA MlTOS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NVnNVZRNOC5zLUCuOUDPxE1? NGLkXWg6KGR? M2i3[JJm\HWlZYOgeIhmKHOrenWsJIlvfmG|aY\lcoV{eyCjbnSgZ4VtdCCwdX3i[ZIhd2ZiY3;sc45q\XN? MXyyNFM5OzF7Nx?=
MC38  MkD6S5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? Mk\NOUDPxE1? NEDSPVE2KGR? MVXpcohq[mm2czDj[YxtKGe{b4f0bEBqdiCjIITpcYUu\GWyZX7k[Y51KG2jbn7ldi=> NYPRdJR[OTl7MEm3OFQ>
U937 MnXtS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NVK0THJyPS1{MDFOwG0> MkXONlQuPzJiaB?= MWLpcohq[mm2czDj[YxtKGe{b4f0bEB{dGmpaITsfS=> MX[xPFQ6OjFzMx?=
HLE  MWTDfZRwfG:6aYT5JGF{e2G7 MnrrNE4xODFvMkCg{txO MlL1OFghcA>? NIm2e|FqdmS3Y3XzJINmdGxiY4n0c5RwgGm2eTDpckBiKGSxc3Wt[IVx\W6mZX70JI1idm6nch?= MmDlNVg{OTh2NEO=
HLF NXT2[FAyS3m2b4TvfIl1gSCDc4PhfS=> M3LXOFAvODBzLUKwJO69VQ>? M4\wfVQ5KGh? Ml7VbY5lfWOnczDj[YxtKGO7dH;0c5hqfHliaX6gZUBld3OnLXTldIVv\GWwdDDtZY5v\XJ? NX;TNFlSOTh|MUi0OFM>

... Click to View More Cell Line Experimental Data

In vivo試験 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]
臨床試験
特集

プロトコル (参考用のみ)

細胞アッセイ: [1]

細胞株 Colo357FG/GLT, and Colo357L3.6pl/GLT
濃度 Dissolved in DMSO, final concentrations ~10 μM
反応時間 48 hours
実験の流れ 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.

動物実験: [1]

動物モデル Athymic nude mice with orthotopic implantation of L3.6pl/GLT cells
製剤 Dissolved in the SX-1292 oral vehicle containing 1% sodium carboxymethylcellulose, 0.5% sodium lauryl sulfate, and 0.05% antifoam
投薬量 50 mg/kg
投与方法 Twice a day p.o.

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

SpeciesMouseRatRabbitGuinea pigHamsterDogMonkeyBaboon
Weight (kg)0.020.151.80.40.0810312
Body Surface Area (m2)0.0070.0250.150.050.020.50.240.6
Km factor361285201220
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

参考

化学情報

Download LY2109761 SDF
分子量 441.52
化学式

C26H27N5O2

CAS No. 700874-71-1
保管 2年-20℃
6月-80℃in solvent
別名 N/A
溶解度 (25°C) * In vitro DMSO 2 mg/mL (4.52 mM)
<1 mg/mL (<1 mM)
エタノール <1 mg/mL (<1 mM)
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.
化学名 7-(2-morpholinoethoxy)-4-(2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)quinoline

カスタマーフィードバック (3)


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Rating
Source Toxicology, 2014, 326C, 9-17. LY2109761 purchased from Selleck
Method Western blot
Cell Lines HepG2 cells
Concentrations 10 uM
Incubation Time 2 h
Results LY2109761, an inhibitor of TGF-β receptor kinase, blocked the galangin-induced increase in LC3-II and attenuated GFP-LC3 focus formation in HepG2 cells.

Click to enlarge
Rating
Source Invest Ophthalmol Vis Sci, 2014, 55(3), 1770-9. LY2109761 purchased from Selleck
Method Morphology
Cell Lines EBV-HCECs
Concentrations 100 nM
Incubation Time 48 h
Results To test the functional relevance of the activation of TGF-β1 signaling, we investigated the effect of a dual TGF-β R1/R2 inhibitor (LY2109761) or anti–TGF-β1 neutralizing antibody on the differentiation of EBV-HCECs. The LY2109761 or anti–TGF-β1 neutralizing antibody treatment changed the morphology of EBV-HCECs from fibroblast-like shapes to epithelial pebble-like shapes.

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Rating
Source PLoS One, 2013, 8(12), e83521. LY2109761 purchased from Selleck
Method Apoptosis assay
Cell Lines AD cells
Concentrations 5 uM
Incubation Time 24 h
Results Treatment of Id2-suppressed AD cells with 1D11 (TGFb neutralizing antibody) orLY2109761 (TGFb type I/II receptor inhibitor) induced remarkable apoptosis (+615% by 1D11 and +553% by LY2109761).

文献中の引用 (6)

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
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