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 MnHpS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MoHITWM2OD1yLkC3NlQ5KM7:TR?= M1vFW3NCVkeHUh?=
HCE-T NILXUIJIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= M3vk[GlEPTB;MT6zNlI1PyEQvF2= MljiV2FPT0WU
D-542MG MWPHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NVvkPGY1UUN3ME2xMlg3PzN5IN88US=> M4Lac3NCVkeHUh?=
23132-87 MXzHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MYPJR|UxRTRwNECxOFch|ryP NWO2PWlIW0GQR1XS
HDLM-2 Ml3XS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NF;aRXBKSzVyPUiuNFQ4PjZizszN MWfTRW5ITVJ?
ACN MVLHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? Mm\KTWM2OD16LkWwNVA6KM7:TR?= MWLTRW5ITVJ?
HuO-3N1 MkXyS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NEPvTohKSzVyPUmuOlAyODhizszN MofJV2FPT0WU
BHT-101 MlfES5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MkPBTWM2OD1zMT6zPEDPxE1? NIrvRWVUSU6JRWK=
KYSE-150 MkDYS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MlLsTWM2OD1zMT61PFQyKM7:TR?= M{OzT3NCVkeHUh?=
MC-IXC NGrWPFBIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= M1K5XGlEPTB;MUKuNlI6OiEQvF2= MYLTRW5ITVJ?
D-423MG MkL5S5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MVPJR|UxRTF{Lke2OVch|ryP NVvYdZFQW0GQR1XS
NY NGnS[otIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= M4O4TGlEPTB;MUSuPFkxOyEQvF2= M37lW3NCVkeHUh?=
HOS MYLHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NFTQXFVKSzVyPUG1MlY4OTlizszN MVvTRW5ITVJ?
NB7 MXHHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? M1PvcGlEPTB;MUWuPFkyKM7:TR?= M2\GV3NCVkeHUh?=
DMS-273 NIHLbG1Iem:5dHigTY5pcWKrdHnvckBCe3OjeR?= M{W1PWlEPTB;MU[uOlcyOyEQvF2= MorXV2FPT0WU
MDA-MB-361 MnfDS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? Mo\HTWM2OD1zNz6yO|EyKM7:TR?= MnfQV2FPT0WU
DU-145 NVXNU4o5T3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= M2LibmlEPTB;MUiuN|Ih|ryP MnzPV2FPT0WU
NCI-H82 MYTHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? M1TWW2lEPTB;MUmuPFM5PiEQvF2= NVviOGp5W0GQR1XS
NCI-SNU-1 NIrIOWdIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NX3VSnFnUUN3ME2yNE4xOTl4IN88US=> M1zTUXNCVkeHUh?=
GCT NYDVNGVWT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= M1L6fmlEPTB;MkCuPFgzPCEQvF2= NX:4fVFjW0GQR1XS
C2BBe1 NVjmdpRJT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NXqwb25{UUN3ME2yNU4yODV6IN88US=> M4DMfHNCVkeHUh?=
LB2241-RCC NWXpOFd1T3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NXvKeWNTUUN3ME2yNU45PDRzIN88US=> MXPTRW5ITVJ?
COLO-829 M2\qS2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7 M13TVmlEPTB;MkKuNVg4OSEQvF2= NUf1NIkzW0GQR1XS
EW-11 MXzHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NXnFUVdGUUN3ME2yNk45ODJ{IN88US=> NHi4e4xUSU6JRWK=
NCI-H526 M3LOc2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7 M{Lxe2lEPTB;MkOuOFcyPyEQvF2= MV;TRW5ITVJ?
SF295 MnfiS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MYLJR|UxRTJ2LkCyOVIh|ryP MULTRW5ITVJ?
D-566MG MXzHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? M{TPfWlEPTB;MkWuNlk1OyEQvF2= M4TyV3NCVkeHUh?=
8505C NFfJV4dIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MYnJR|UxRTJ3Lk[zN|Eh|ryP M4PVTXNCVkeHUh?=
HT-29 MUfHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? M3PrSmlEPTB;Mk[uNFQ{OSEQvF2= M{jRSnNCVkeHUh?=
NBsusSR M3TSV2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MknJTWM2OD1{Nj64NFA3KM7:TR?= NXPGfm9IW0GQR1XS
BV-173 NIPBXmtIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NYfYNm9OUUN3ME2yPE4{OTh{IN88US=> Mm\MV2FPT0WU
CTB-1 NVLzVZk1T3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NVfLe3pGUUN3ME2zNE4yODNzIN88US=> M4fLU3NCVkeHUh?=
JAR NVjtWmdxT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MWfJR|UxRTN{LkWzO|Eh|ryP M170O3NCVkeHUh?=
CAMA-1 NXPQfHpxT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MlntTWM2OD1|Mz60OlE2KM7:TR?= M1TjeHNCVkeHUh?=
CAL-51 M1PZPGdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NH3DfYdKSzVyPUO0MlcyPzZizszN NF7YVFlUSU6JRWK=
A172 MnXqS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NHzTWlVKSzVyPUO3MlQ6OjFizszN NX\0WYlSW0GQR1XS
QIMR-WIL NXu2VGtWT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MoO0TWM2OD1|OD6wO|A5KM7:TR?= MoLmV2FPT0WU
AsPC-1 M17Dcmdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MlHSTWM2OD1|OD60OlUyKM7:TR?= NX[5coFNW0GQR1XS
MKN7 M4XuVmdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MoO3TWM2OD1|OT6wNFc6KM7:TR?= MnnQV2FPT0WU
ONS-76 NV3nW3RqT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MlTNTWM2OD12Mz6zNFU4KM7:TR?= NHvKW|JUSU6JRWK=
RS4-11 NVjqO2RvT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NIjve3BKSzVyPUS0MlA4PTJizszN MnvoV2FPT0WU
NOS-1 NUDnd4RbT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= M2rsemlEPTB;NESuOlA{OSEQvF2= NF7CSHRUSU6JRWK=
A101D MWXHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NGr4fY1KSzVyPUS0MlgxOjNizszN MUPTRW5ITVJ?
HCC1806 MoP6S5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NVrGPYpnUUN3ME20Ok4yOTR6IN88US=> NFLXdIVUSU6JRWK=
CAL-27 M2jDO2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MVnJR|UxRTR5LkeyOFYh|ryP M3L3fXNCVkeHUh?=
BT-549 M1H1dGdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MmTzTWM2OD12OD61N|E2KM7:TR?= MkfWV2FPT0WU
LCLC-97TM1 MkjzS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? Ml25TWM2OD12OT6yOFE{KM7:TR?= MojKV2FPT0WU
A4-Fuk NWW3Um1xT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NEfESmRKSzVyPUS5Mlg1QSEQvF2= MXHTRW5ITVJ?
OVCAR-4 M3PIcGdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NVfGSHRiUUN3ME21NE4xPjBzIN88US=> NHHnfFJUSU6JRWK=
HD-MY-Z MkHJS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MV\JR|UxRTVyLke3OlQh|ryP M4jGXnNCVkeHUh?=
NCI-H292 M4rL[Gdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NF7BZoxKSzVyPUWwMlg4PThizszN MX;TRW5ITVJ?
Sk-ChA-1  M4\obGdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 M2fQS|AvOjYkgKO1NEDPxE1? NHmyT404OiCq NHrhfZhKSzVyPUe0MlU1yrF{LkW4{txO MXuyOVc1OjR6Mh?=
Mz-ChA-1 M{XZV2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NH;INpAxNjJ34pETOVAh|ryP NV76dpRWPzJiaB?= M1f6WmlEPTB;NUSuPVfDuTNwNEZOwG0> MVOyOVc1OjR6Mh?=
Smo-WT Ml[0S5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MX;JR|UxyqCxZjCxOOKhdk1? NUjTXoFSOjR{OUGxNFQ>
Smo-D473H  NIDwOFFIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MXjJR|UxyqCxZjC3MlHDqM7:TR?= Mn3rNlQzQTFzMES=
K562 MmnlSpVv[3Srb36gRZN{[Xl? NVnSR3NLOTBizszN MXS3NkBp M13GOJJm\HWlZYOgeIhmKGW6cILld5Nqd25ib3[gS4xqOcLi MX[yN|MyQTh{NB?=
T315I BCR-ABL BaF3 MUXGeY5kfGmxbjDBd5NigQ>? MkXWNVAh|ryP NUXMNINFPzJiaB?= NYLJSmo6emWmdXPld{B1cGViZYjwdoV{e2mxbjDv[kBIdGlzwrC= NED1Z3gzOzNzOUiyOC=>
TF-1 BCR-ABL NGXlPVdHfW6ldHnvckBCe3OjeR?= Mli4NVAh|ryP NWHEZmhKPzJiaB?= NUn4foZOemWmdXPld{B1cGViZYjwdoV{e2mxbjDv[kBIdGlzwrC= MXOyN|MyQTh{NB?=

... 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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Rating
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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Rating
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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Rating
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 ).

Click to enlarge
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.

Click to enlarge
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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Rating
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 (32)

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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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