Vismodegib (GDC-0449) 化学構造
分子量: 421.3

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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 Vismodegib (GDC-0449)は、強力で、新しくて、特定のハリネズミ経路阻害剤で、 IC50 が 3 nMになる。
ターゲット Hedgehog
IC50 3 nM [1]
In vitro試験 GDC-0449 targets the Hedgehog signaling pathway, blocking the activities of the Hedgehog-ligand cell surface receptors PTCH and/or SMO and suppressing Hedgehog signaling. GDC-0449 prevents multiple ATP-binding cassette (ABC) transporters. GDC-0449 also blocks ABCG2, Pgp, and MRP1-important ABC transporters associated with MDR. GDC-0449 is a potent inhibitor of ABC transporters, ABCG2/BCRP and ABCB1/Pgp, and is a mild inhibitor of ABCC1/MRP1. In ABCG2-overexpressing HEK293 cells, GDC-0449 increases retention of the fluorescent ABCG2 substrate BODIPY-prazosin and resensitizes these cells to mitoxantrone. In Madin-Darby canine kidney II cells engineered to overexpress Pgp or MRP1, GDC-0449 increases the retention of calcein-AM and resensitizes them to colchicine. GDC-0449 also resensitizes human non-small cell lung carcinoma cells NCI-H460/par and NCI-H460/MX20, which overexpress ABCG2 in response to mitoxantrone, to mitoxantrone, and to topotecan or SN-38. The IC50 values of GDC-0449 for prevention of ABCG2 and Pgp are about 1.4 μM and 3.0 μM, respectively. [2] GDC-0449 alters intracellular Ca2+ homeostasis and inhibits cell growth in cisplatin-resistant lung cancer cells. [3]
Cell Data
Cell LinesAssay TypeConcentrationIncubation TimeFormulationActivity DescriptionPMID
IGROV-1 MUDHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NVnsV5FwUUN3ME2wMlA4OjR6IN88US=> MlPpV2FPT0WU
HCE-T M1rnSGdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 M2TEd2lEPTB;MT6zNlI1PyEQvF2= MoHmV2FPT0WU
D-542MG MofzS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MVnJR|UxRTFwOE[3N|ch|ryP NETOfW1USU6JRWK=
23132-87 MYPHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NWPjTJFUUUN3ME20MlQxOTR5IN88US=> NGjpOJVUSU6JRWK=
HDLM-2 NWGwOW5tT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MkPSTWM2OD16LkC0O|Y3KM7:TR?= MkPtV2FPT0WU
ACN MWDHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NVTLOmh5UUN3ME24MlUxOTB7IN88US=> NEPJXY1USU6JRWK=
HuO-3N1 M{D2UGdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NH3j[YVKSzVyPUmuOlAyODhizszN NGnjb4VUSU6JRWK=
BHT-101 NHq1cYlIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NFXVPXRKSzVyPUGxMlM5KM7:TR?= NWrPN|dGW0GQR1XS
KYSE-150 NGnjNpdIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NVjv[2ZzUUN3ME2xNU42QDRzIN88US=> M1uxcHNCVkeHUh?=
MC-IXC M13K[Gdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MVHJR|UxRTF{LkKyPVIh|ryP M2DadXNCVkeHUh?=
D-423MG NHvjT21Iem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NE\Td49KSzVyPUGyMlc3PTdizszN NEjpdZJUSU6JRWK=
NY MV;Hdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NY\Wd2ExUUN3ME2xOE45QTB|IN88US=> MoDSV2FPT0WU
HOS NIi5ZVZIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MUXJR|UxRTF3Lk[3NVkh|ryP M4HSWXNCVkeHUh?=
NB7 MlzYS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? M3nDSmlEPTB;MUWuPFkyKM7:TR?= MUfTRW5ITVJ?
DMS-273 M4LaOWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NFvNU3VKSzVyPUG2MlY4OTNizszN M1vR[3NCVkeHUh?=
MDA-MB-361 M4P0Xmdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 M33nUGlEPTB;MUeuNlcyOSEQvF2= Mmj4V2FPT0WU
DU-145 M2nSN2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MXzJR|UxRTF6LkOyJO69VQ>? MWPTRW5ITVJ?
NCI-H82 MlrlS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MoPvTWM2OD1zOT64N|g3KM7:TR?= NYHtW4dtW0GQR1XS
NCI-SNU-1 NXfjSY5YT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NFqz[GFKSzVyPUKwMlAyQTZizszN MmThV2FPT0WU
GCT NXnjdnZjT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= M4\zWWlEPTB;MkCuPFgzPCEQvF2= M1TZenNCVkeHUh?=
C2BBe1 MU\Hdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MUfJR|UxRTJzLkGwOVgh|ryP MmfUV2FPT0WU
LB2241-RCC MlWzS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? M{nTT2lEPTB;MkGuPFQ1OSEQvF2= NUDF[XdWW0GQR1XS
COLO-829 M3HqOmdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MlT2TWM2OD1{Mj6xPFcyKM7:TR?= M3K5bHNCVkeHUh?=
EW-11 NX;4SVRST3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MUXJR|UxRTJ{LkiwNlIh|ryP MYDTRW5ITVJ?
NCI-H526 M1PzTGdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MV;JR|UxRTJ|LkS3NVch|ryP NXvlSHZ4W0GQR1XS
SF295 NWD3XZFtT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= M4r3ZWlEPTB;MkSuNFI2OiEQvF2= M{LNZnNCVkeHUh?=
D-566MG NYjSSWhsT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= M1n2cmlEPTB;MkWuNlk1OyEQvF2= NYHRWodmW0GQR1XS
8505C MoraS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? Mk\ITWM2OD1{NT62N|MyKM7:TR?= M4PpSXNCVkeHUh?=
HT-29 M1HXcWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MXHJR|UxRTJ4LkC0N|Eh|ryP NVjVcGdMW0GQR1XS
NBsusSR MkTJS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MVnJR|UxRTJ4LkiwNFYh|ryP NITVWVRUSU6JRWK=
BV-173 MY\Hdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? Mo[3TWM2OD1{OD6zNVgzKM7:TR?= M2rYVXNCVkeHUh?=
CTB-1 NUfVTHEzT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MV;JR|UxRTNyLkGwN|Eh|ryP NFj4b2JUSU6JRWK=
JAR MoL4S5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? M3LTc2lEPTB;M{KuOVM4OSEQvF2= NELtO2hUSU6JRWK=
CAMA-1 NETWR5pIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MoH5TWM2OD1|Mz60OlE2KM7:TR?= MXTTRW5ITVJ?
CAL-51 MnPtS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NXzPfZZYUUN3ME2zOE44OTd4IN88US=> MlvOV2FPT0WU
A172 NHHUOJpIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= M1H1XGlEPTB;M{euOFkzOSEQvF2= M{LYVnNCVkeHUh?=
QIMR-WIL NWTxUlJTT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= M165R2lEPTB;M{iuNFcxQCEQvF2= NVvJTY9XW0GQR1XS
AsPC-1 MWDHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NWjuUXVvUUN3ME2zPE41PjVzIN88US=> NGfMc4JUSU6JRWK=
MKN7 NGPnZVBIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MkXnTWM2OD1|OT6wNFc6KM7:TR?= NVO3T40zW0GQR1XS
ONS-76 NYe1blMxT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MWfJR|UxRTR|LkOwOVch|ryP MoTSV2FPT0WU
RS4-11 NECyRolIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= M2TXNmlEPTB;NESuNFc2OiEQvF2= M3PDTnNCVkeHUh?=
NOS-1 MX3Hdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NF;BTFlKSzVyPUS0MlYxOzFizszN M1zQeHNCVkeHUh?=
A101D MX;Hdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NWnZSnRQUUN3ME20OE45ODJ|IN88US=> NYHqVZNZW0GQR1XS
HCC1806 NXLOVY1FT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= M1Tid2lEPTB;NE[uNVE1QCEQvF2= NULRN3FqW0GQR1XS
CAL-27 MmX6S5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MlPXTWM2OD12Nz63NlQ3KM7:TR?= MnrxV2FPT0WU
BT-549 NVfk[GFlT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MV\JR|UxRTR6LkWzNVUh|ryP Ml3zV2FPT0WU
LCLC-97TM1 M{\Demdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MV\JR|UxRTR7LkK0NVMh|ryP M{m3OHNCVkeHUh?=
A4-Fuk Mlr1S5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MlrOTWM2OD12OT64OFkh|ryP MnPUV2FPT0WU
OVCAR-4 NF;MNldIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MVjJR|UxRTVyLkC2NFEh|ryP NH3ySHBUSU6JRWK=
HD-MY-Z NXe5SlVJT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MlnrTWM2OD13MD63O|Y1KM7:TR?= M3TvSXNCVkeHUh?=
NCI-H292 MV\Hdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MV7JR|UxRTVyLki3OVgh|ryP NGXFW3ZUSU6JRWK=
Sk-ChA-1  MUjHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MYewMlI26oDVNUCg{txO NVLPRVRyPzJiaB?= MUnJR|UxRTd2LkW0xtEzNjV6zszN M1jVZ|I2PzR{NEiy
Mz-ChA-1 MWnHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? Mm\NNE4zPeLCk{WwJO69VQ>? NEPNPJI4OiCq NHLWRVFKSzVyPUW0Mlk4yrF|LkS1{txO NYjnZ3I1OjV5NEK0PFI>
Smo-WT MX7Hdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NIfGOpFKSzVywrDv[kAyPMLibl2= NV62N4lFOjR{OUGxNFQ>
Smo-D473H  MWXHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MknFTWM2OMLib3[gO{4yyqEQvF2= NWXH[VJIOjR{OUGxNFQ>
K562 NFvkbHBHfW6ldHnvckBCe3OjeR?= MV[xNEDPxE1? NH[zcIQ4OiCq MkjNdoVlfWOnczD0bIUh\XiycnXzd4lwdiCxZjDHcIkyyqB? Ml7lNlM{OTl6MkS=
T315I BCR-ABL BaF3 NXHnbZRoTnWwY4Tpc44hSXO|YYm= NGnoSIQyOCEQvF2= M3PiPFczKGh? NH;yVJZz\WS3Y3XzJJRp\SCneIDy[ZN{cW:wIH;mJGdtcTIEoB?= NGXXSGozOzNzOUiyOC=>
TF-1 BCR-ABL Ml7oSpVv[3Srb36gRZN{[Xl? MXWxNEDPxE1? NEfjOG84OiCq M4fIOpJm\HWlZYOgeIhmKGW6cILld5Nqd25ib3[gS4xqOcLi NYeyRY9{OjN|MUm4NlQ>

... Click to View More Cell Line Experimental Data

In vivo試験 GDC-0449 has been used to treat medulloblastoma in animal models. [2] GDC-0449 prevents the growth of primary pancreatic xenografts without non-specifically inhibiting pancreatic cell proliferation. Oral dosing of GDC-0449 causes tumor regressions in the Ptch(+/-) allograft model of medulloblastoma at doses ≥25 mg/kg and tumor growth inhibition at doses up to 92 mg/kg dosed twice daily in two ligand-dependent colorectal cancer models, D5123, and 1040830. Analysis of Hh pathway activity and PK/PD modeling reveals that GDC-0449 inhibits Gli1 with a similar IC50 in both the medulloblastoma and D5123 models (0.165 μM and 0.267 μM, respectively). Pathway modulation is linked to efficacy using an integrated PK/PD model revealing a steep relationship where > 50% of the activity of GDC-0449 is associated with >80% repression of the Hh pathway. [4]
臨床試験 GDC-0449 has entered into a phase II clinical trials in the treatment of basal cell carcinoma.
特集

プロトコル (参考用のみ)

細胞アッセイ: [2]

細胞株 MDCKII cells
濃度 20 μM
反応時間 2 hours
実験の流れ MDCKII cells are seeded into 24-well plates at a density of 3 × 105 cells per well and are allowed to attach. Medium is then changed to that containing different drugs (50 μM VP, 50 μM indomethacin, or 20 μM GDC-0449 in DMSO or DMSO alone as control, and nonfluorescent calcein-AM is added to a final concentration of 1.0 μM and incubated at 37 °C for 2 hours. Cells are then washed twice with Ca2+, Mg2+-containing Hank's balanced salt solution buffer and lysed by shaking in 0.01% Triton X-100 in PBS buffer for 1 hour at room temperature or overnight at 4 °C. The lysate is then transferred into 96-well plates, and the fluorescence signal caused by the cell-derived calcein is quantified spectrophotometrically with a SpectraMax M5 Multi-Detection Readerusing an excitation wavelength of 495 nm and an emission wavelength of 515 nm. All manipulations are performed in the dark. All readings are expressed as mean ?SEM normalized to the control.

動物実験: [4]

動物モデル Ptch(+/-) allograft model, D5123 and 1040830
製剤 In 0.5% methyl-cellulose, 0.2% tween-80
投薬量 ~ 100 mg/kg
投与方法 Orally

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 Vismodegib (GDC-0449) SDF
分子量 421.3
化学式

C19H14Cl2N2O3S

CAS No. 879085-55-9
保管 2年-20℃
6月-80℃in solvent
別名 N/A
溶解度 (25°C) * In vitro DMSO 84 mg/mL (199.38 mM)
<1 mg/mL (<1 mM)
エタノール <1 mg/mL (<1 mM)
In vivo 0.5% methylcellulose+0.2% Tween 80 30 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 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide

カスタマーフィードバック (15)


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Rating
Source Gastroenterology, 2012, 143, 1319-29. Vismodegib (GDC-0449) purchased from Selleck
Method qRT-PCR/immunostaining
Cell Lines MF-HSCs
Concentrations 1 μM
Incubation Time 4 d
Results Conditional deletion of SMO in MF-HSCs recapitulated the effects of GDC-0449, causing significant down-regulation of glyco-lytic genes and MF genes.

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Source Gastroenterology, 2012, 143, 1319-29. Vismodegib (GDC-0449) purchased from Selleck
Method Immunohistochemistry
Cell Lines MDR2 -/- mice
Concentrations 1 μM
Incubation Time 4 d
Results We found that treating year-old MDR2 -/- mice with a 9-day course of GDC-0449 substantially reduced the numbers of PKM2-positive cells despite the ongoing genetic stimulus for liver repair.

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Source Gut, 2013, 62, 299-309. Vismodegib (GDC-0449) purchased from Selleck
Method Immunohistochemistry
Cell Lines Mdr2 -/- mice/hepatectomised mice
Concentrations
Incubation Time
Results Treatment of Mdr2 -/- mice with GDC-0449 (Hh signalling antagonist) significantly reduced the number of Gli2 and CD31 (a commonly used capillarisation marker in vivo) double-positive cells in the liver (figure A,B). Similar results were observed in partial hepatectomised mice treated with cyclopamine ( figure C).

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Source Hepatology, 2011, 54, 1580-90. Vismodegib (GDC-0449) purchased from Selleck
Method qRT-PCR/Western blot
Cell Lines Huh7.5 cells
Concentrations 0-5 μM
Incubation Time 72 h
Results GDC-0449, a preclinical Hh pathway inhibitor, inhibits replication of JFH1 HCV in a dose-response manner.

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Rating
Source Cancer Res, 2012, 72, 5912-20. Vismodegib (GDC-0449) purchased from Selleck
Method qRT-PCR/Western blot
Cell Lines HepG2/Huh7 cells
Concentrations 1 μmol/L
Incubation Time
Results GDC-0449 treatment of HepG2X cells decreased mRNA levels of Shh by 2.6-fold (61%, P < 0.005), PTCH1 by 6.8-fold (85%, P < 0.05), and Gli2 by 2.4-fold (58%, P < 0.05). GDC-0449 reduced Gli2 in HepG2X cells (2.2-fold; 55%, P < 0.02) and in Huh7X cells (3.8-fold; 74%, P < 0.02), but not in treated compared with untreated control cells (Fig. 1). GDC-0449 also reduced PTCH1 in HepG2X (1.8-fold; 44%, P < 0.02) and Huh7X cells (2.6-fold; 61%, P < 0.01), but not in the HBx negative cultures. Hence, HBx stimulates expression of Hhcomponents in human liver cancer cells.

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Rating
Source Cancer Res, 2013, 72, 5912-20. Vismodegib (GDC-0449) purchased from Selleck
Method Phenotypic assays
Cell Lines HBx positive/negative cells
Concentrations 1 μmol/L
Incubation Time
Results GDC-0449 decreased the clonability of Huh7X cells by 2.2-fold compared with untreated cells (P < 0.01), and of HepG2X cells by 1.8-fold compared with untreated cells.

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Source Cancer Res, 2014, 72, 5912-20. Vismodegib (GDC-0449) purchased from Selleck
Method Western blot/Immunohistochemistry
Cell Lines Twelve-month-old mice
Concentrations
Incubation Time
Results Untreated 12-month-old HBxTg had multiple tumors on the surface of their livers (Fig. A) although most GDC-0449-treated m ice had fewer tumors. These differences were statistically significant (Fig. B). Excised tumors showed lower levels of Gli2 in GDC- 0449-treated mice compared with controls(Fig. C).The latter was confirmed by staining , where no Gli2 was observed in treated compared with untreated mice (Fig . D).

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Source Chem Biol, 2012, 19, 972-82. Vismodegib (GDC-0449) purchased from Selleck
Method Hh Activity Assays
Cell Lines ShhLightII cells/SmoM2 cells
Concentrations 0-10 μM
Incubation Time 6 h
Results Hh pathway inhibition by GDC0449, Cyc and SANT-1, as measured by both Gliluciferase induction (Figure A) and Smo ciliary localization ( Figures B and C), was dramatically reduced in vitro in the presence of FA. Thus, FA cotreatment leads to a drug-dependent alteration of cellular response to chemical inhibitors of Smo. This may occur through competition, or the requirement for a higher level of GDC-0449 to inhibit Hh-driven pathway activity in the presence of GC, but the outcome resembles the genetic resistance seen with a dominant active Smo mutation SmoM2) (Figure A).

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Rating
Source Chem Biol, 2012, 19, 972-82. Vismodegib (GDC-0449) purchased from Selleck
Method Hh Activity Assays
Cell Lines Smo::EGFP/Iv s::tagRFPT cells
Concentrations 0-1000 nM
Incubation Time
Results Bud enhanced GDC0449’s activity to block Smo accumulation at the PC and Hh pathway inhibition.

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Rating
Source PLoS One, 2013, 8, e74141. Vismodegib (GDC-0449) purchased from Selleck
Method H&E staining, Western blot
Cell Lines C6
Concentrations 1-20 uM
Incubation Time 24 h
Results GDC-0449 inhibited the activation of Hh signaling in the irradiated livers.

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Rating
Source PLoS One, 2011, 6, e23943. Vismodegib (GDC-0449) purchased from Selleck
Method Immunohistochemistry/qRT-PCR
Cell Lines MDR2 -/- mice
Concentrations 40 mg/kg
Incubation Time 9 d
Results Overall survival between the two groups in the second cohort was equal, with no deaths in the DMSO treatment group and 1 death in the GDC-0449 treatment group secondary to iatrogenic injury. Both the liver parenchyma and tumors of treated mice showed decreased expression of the Hh pathway target Gli2 ( Figures A–B). Real-time PCR analysis of resected tumors revealed that GDC-0449 treatment released the inhibitory effects of Hh signaling on PPARa ˜ , causing a significant increase in its gene expression ( Figure C). Treatment with GDC-0449 also caused a significant decrease in expression of Gli1, another Hh target gene (Figure D ).

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Rating
Source PLoS One, 2011, 6, e23943. Vismodegib (GDC-0449) purchased from Selleck
Method Immunohistochemistry
Cell Lines MDR2 -/- mice
Concentrations 40 mg/kg
Incubation Time 9 d
Results Treatment with GDC-0449 decreased α-sma-expressing myofibroblastic cells, hepatic expression of TGF- β andPDGF- β, Sirius red staining, and hydroxyproline content, demonstrating that Hh pathway inhibition reduced liver fibrosis.

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Rating
Source PLoS One, 2011, 6, e23943. Vismodegib (GDC-0449) purchased from Selleck
Method Immunohistochemistry/QRT-PCR analysis
Cell Lines MDR2 -/- mice
Concentrations 40 mg/kg
Incubation Time 9 d
Results Immunohistochemistry and quantitative morphometry demonstrated that inhibition of the Hh pathway with GDC-0449 significantly decreased osteopontin staining within primary liver tumors ( Figure A ). Similar treatment-related decreases in CD44 + tumor cells were also noted (Figure B). Gene expression analysis showed that expression of both osteopontin and CD44 mRNAs also tended to decrease in GDC-0449-treated mice ( Figure C ).

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Source J Neuroncol , 2011, 105, 475-483. Vismodegib (GDC-0449) purchased from Selleck
Method Quantitative RT-PCR
Cell Lines Mouse medulloblastoma primary cells (U51669)
Concentrations 0-100 nM
Incubation Time
Results GDC-0449 effectively suppressed Gli1, which is a Shh pathway target gene.

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Rating
Source Vismodegib (GDC-0449) purchased from Selleck
Method Flow cytometry
Cell Lines ABCG2-expressing cell sublines
Concentrations 50 µM
Incubation Time
Results We examined the inhibition of Pp-18 efflux to assess reported inhibitors of ABCG2-mediated drug resistance. The fold value is defined as the accumulation of Pp-18 in the presence of an inhibitor divided by the accumulation of Pp-18 in the absence of an inhibitor. vismodegib demonstrated a significant increase in Pp-18 accumulation in both human and mouse ABCG2-expressing cell lines.

文献中の引用 (33)

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Related ヘッジホッグ/スムーズンド 阻害剤

  • Smoothened Agonist (SAG) HCl

    Smoothened Agonist (SAG) HCl is a cell-permeable Smoothened (Smo) agonist.

  • SB225002

    SB225002 is a potent, and selective CXCR2 antagonist with IC50 of 22 nM for inhibiting interleukin IL-8 binding to CXCR2, > 150-fold selectivity over the other 7-TMRs tested.

  • SB-334867

    SB-334867 is a selective orexin-1 (OX1) receptor antagonist.

  • BAF312 (Siponimod)

    BAF312 (Siponimod) is a next-generation S1P receptor modulator, selective for S1P1 and S1P5 receptors with EC50 of 0.39 nM and 0.98 nM, respectively.

  • Cyclopamine

    Cyclopamineは、スムーズにされる(SMO)ものの経路敵対者に合図している特定のハリネズミ(Hh)で、 IC50 が 46 nM。

  • GANT61

    GANT61 is an inhibitor for GLI1 as well as GLI2-induced transcription, inhibits hedgehog with IC50 of 5 μM, displays selectivity over other pathways, such as TNF and glucocorticoid receptor gene transactivation.

  • Purmorphamine

    Purmorphamine, which directly binds and activates Smoothened, blocks BODIPY-cyclopamine binding to Smo with IC50 of ~ 1.5 μM and also is an inducer of osteoblast differentiation with EC50 of 1 μM.

  • LDE225 (NVP-LDE225,Erismodegib)

    LDE225 (NVP-LDE225,Erismodegib)は、スムーズにされた 敵対者で、IC50 がそれぞれ 1.3 nM (mouse)と 2.5 nM (human)です。

  • Taladegib (LY2940680)

    Taladegib (LY2940680)はSmoレセプターと結合して、強力にHhシグナリングを妨げます。

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
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