Vismodegib (GDC-0449) 化学構造
分子量: 421.3

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製品説明

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    Hedgehog/Smoothened製品生物活性の比較
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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 M3Hvcmdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MYTJR|UxRTBwMEeyOFgh|ryP Ml\RV2FPT0WU
HCE-T NF\oS4JIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NYTzVpNrUUN3ME2xMlMzOjR5IN88US=> NUew[Hh7W0GQR1XS
D-542MG NV\EPZVvT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NHXpU3hKSzVyPUGuPFY4OzdizszN MX7TRW5ITVJ?
23132-87 NEjyd|NIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NETKTYVKSzVyPUSuOFAyPDdizszN NHT2UmRUSU6JRWK=
HDLM-2 MkDZS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NFHqV2RKSzVyPUiuNFQ4PjZizszN NVPjSoVCW0GQR1XS
ACN NH3wRopIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NF3COmdKSzVyPUiuOVAyODlizszN MlLuV2FPT0WU
HuO-3N1 NX;2Z4w{T3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= M1XJe2lEPTB;OT62NFExQCEQvF2= NYjvPWd6W0GQR1XS
BHT-101 M3rERmdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NG\CVnhKSzVyPUGxMlM5KM7:TR?= Mm[1V2FPT0WU
KYSE-150 NFS3OHpIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= M2LmRWlEPTB;MUGuOVg1OSEQvF2= NIjnUXBUSU6JRWK=
MC-IXC NVvscWloT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MVvJR|UxRTF{LkKyPVIh|ryP NFjJfYZUSU6JRWK=
D-423MG MlHTS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MmLGTWM2OD1zMj63OlU4KM7:TR?= M2OzN3NCVkeHUh?=
NY NILKfJFIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= M3m5V2lEPTB;MUSuPFkxOyEQvF2= NXXXXWVqW0GQR1XS
HOS NU\TOVB4T3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= M3yz[2lEPTB;MUWuOlcyQSEQvF2= NIX1NGlUSU6JRWK=
NB7 NX3MTZRGT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NXPuUmtMUUN3ME2xOU45QTFizszN M{TqTHNCVkeHUh?=
DMS-273 NGTsbJVIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NYP6cZdLUUN3ME2xOk43PzF|IN88US=> NX[5R|lGW0GQR1XS
MDA-MB-361 MlO2S5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NYPiT4VCUUN3ME2xO{4zPzFzIN88US=> M3LXd3NCVkeHUh?=
DU-145 MYXHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NVLZ[YFSUUN3ME2xPE4{OiEQvF2= MWXTRW5ITVJ?
NCI-H82 MVLHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MXLJR|UxRTF7LkizPFYh|ryP MnjjV2FPT0WU
NCI-SNU-1 MV;Hdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NG\aXVRKSzVyPUKwMlAyQTZizszN NFfmNG9USU6JRWK=
GCT NHPCSIFIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NFnadYpKSzVyPUKwMlg5OjRizszN MXXTRW5ITVJ?
C2BBe1 MYfHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? Mm\oTWM2OD1{MT6xNFU5KM7:TR?= MV3TRW5ITVJ?
LB2241-RCC NG\NZ2dIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NFXIW4FKSzVyPUKxMlg1PDFizszN MUXTRW5ITVJ?
COLO-829 NVvtXGRsT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MVfJR|UxRTJ{LkG4O|Eh|ryP MlLzV2FPT0WU
EW-11 MX;Hdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? M2LoXmlEPTB;MkKuPFAzOiEQvF2= M2LJRnNCVkeHUh?=
NCI-H526 MXHHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NGXQSJVKSzVyPUKzMlQ4OTdizszN MoTZV2FPT0WU
SF295 NVXUVHkzT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MYrJR|UxRTJ2LkCyOVIh|ryP NID1fIZUSU6JRWK=
D-566MG NYD5[oxIT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= Mm\3TWM2OD1{NT6yPVQ{KM7:TR?= NYSxPXRFW0GQR1XS
8505C M4LyO2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MoHsTWM2OD1{NT62N|MyKM7:TR?= MkjzV2FPT0WU
HT-29 MlP3S5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? Ml:3TWM2OD1{Nj6wOFMyKM7:TR?= NHvsZW5USU6JRWK=
NBsusSR NUGx[oRDT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= M17L[mlEPTB;Mk[uPFAxPiEQvF2= NIjBXmVUSU6JRWK=
BV-173 NHv0SmlIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= M2\BVGlEPTB;MkiuN|E5OiEQvF2= M{nLdXNCVkeHUh?=
CTB-1 M2LpO2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NHfpR4FKSzVyPUOwMlExOzFizszN NFXG[olUSU6JRWK=
JAR NV;hNXhLT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MofUTWM2OD1|Mj61N|cyKM7:TR?= NWDyV2toW0GQR1XS
CAMA-1 MUDHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? M1zVNmlEPTB;M{OuOFYyPSEQvF2= NVvSVZNsW0GQR1XS
CAL-51 NHPuTolIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NHvVUVVKSzVyPUO0MlcyPzZizszN M3nsfXNCVkeHUh?=
A172 NWXCRmRNT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MU\JR|UxRTN5LkS5NlEh|ryP NW\MNnBnW0GQR1XS
QIMR-WIL MUPHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MlLhTWM2OD1|OD6wO|A5KM7:TR?= M1O2TnNCVkeHUh?=
AsPC-1 NUC1TGVQT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NVuwdGRlUUN3ME2zPE41PjVzIN88US=> M1z6VnNCVkeHUh?=
MKN7 MYPHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NHrkc5FKSzVyPUO5MlAxPzlizszN NX7ZfHdEW0GQR1XS
ONS-76 MojES5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? Mm\uTWM2OD12Mz6zNFU4KM7:TR?= MWHTRW5ITVJ?
RS4-11 MUXHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NFrMfYNKSzVyPUS0MlA4PTJizszN MUTTRW5ITVJ?
NOS-1 NWTOXGxqT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NXLLWWlKUUN3ME20OE43ODNzIN88US=> NU\RR3BoW0GQR1XS
A101D M{KxdGdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NHnjSGZKSzVyPUS0MlgxOjNizszN M1[5fnNCVkeHUh?=
HCC1806 NITnXotIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NGPMcIpKSzVyPUS2MlEyPDhizszN NF62TVBUSU6JRWK=
CAL-27 NWi5bmlnT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NV7TXpNmUUN3ME20O{44OjR4IN88US=> MVvTRW5ITVJ?
BT-549 M4PVSWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NEHGbZBKSzVyPUS4MlU{OTVizszN NVjOSYF[W0GQR1XS
LCLC-97TM1 MmnCS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NV3pVGtEUUN3ME20PU4zPDF|IN88US=> MlLBV2FPT0WU
A4-Fuk M4nxfWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MYfJR|UxRTR7Lki0PUDPxE1? Mn63V2FPT0WU
OVCAR-4 NU[5VoNUT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= M2\1XGlEPTB;NUCuNFYxOSEQvF2= NX\GbHFNW0GQR1XS
HD-MY-Z Mm\NS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NGr4ZlJKSzVyPUWwMlc4PjRizszN MWPTRW5ITVJ?
NCI-H292 NIfkVopIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NV20OIRmUUN3ME21NE45PzV6IN88US=> MYnTRW5ITVJ?
Sk-ChA-1  NHnzTmhIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MnnXNE4zPeLCk{WwJO69VQ>? Mn7YO|IhcA>? Mn;yTWM2OD15ND61OOKyOi53ON88US=> NVHKW4M2OjV5NEK0PFI>
Mz-ChA-1 NGLQWHVIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MlrINE4zPeLCk{WwJO69VQ>? NV7KUItsPzJiaB?= NF\YVZFKSzVyPUW0Mlk4yrF|LkS1{txO MmPFNlU4PDJ2OEK=
Smo-WT NVfkbYxtT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NGPHRoFKSzVywrDv[kAyPMLibl2= MnXkNlQzQTFzMES=
Smo-D473H  MWnHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? M{O3dmlEPTEEoH;mJFcvOcLizszN MX6yOFI6OTFyNB?=
K562 NV\LSnhjTnWwY4Tpc44hSXO|YYm= MmXxNVAh|ryP M2rNcFczKGh? M4rGN5Jm\HWlZYOgeIhmKGW6cILld5Nqd25ib3[gS4xqOcLi NV3lVYJ7OjN|MUm4NlQ>
T315I BCR-ABL BaF3 NXLxXohITnWwY4Tpc44hSXO|YYm= NY\TTo05OTBizszN NWfaeJV{PzJiaB?= MlPqdoVlfWOnczD0bIUh\XiycnXzd4lwdiCxZjDHcIkyyqB? MnvMNlM{OTl6MkS=
TF-1 BCR-ABL MV3GeY5kfGmxbjDBd5NigQ>? NGXIU3UyOCEQvF2= M1S1bFczKGh? NELIZ2Rz\WS3Y3XzJJRp\SCneIDy[ZN{cW:wIH;mJGdtcTIEoB?= M3Xhe|I{OzF7OEK0

... 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 3年-20℃
2年-80℃in solvent
別名 N/A
溶解度 (25°C) * In vitro DMSO 84 mg/mL (199.38 mM)
Water <1 mg/mL
Ethanol <1 mg/mL
In vivo 2% DMSO+30% PEG 300+5% Tween 80+ddH2O 10mg/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

文献中の引用 (34)

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
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