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 Mn[1S5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NF\Ge|JKSzVyPUCuNFczPDhizszN MoXuV2FPT0WU
HCE-T Mli4S5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NIjHWY9KSzVyPUGuN|IzPDdizszN M4GzVXNCVkeHUh?=
D-542MG MXHHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? M3v4NWlEPTB;MT64Olc{PyEQvF2= MXPTRW5ITVJ?
23132-87 M1PIc2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7 M3faUGlEPTB;ND60NFE1PyEQvF2= M2nIR3NCVkeHUh?=
HDLM-2 M3zUUmdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MYXJR|UxRThwMES3OlYh|ryP NIPTco9USU6JRWK=
ACN MVzHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? M1WybmlEPTB;OD61NFExQSEQvF2= NXqyOIwzW0GQR1XS
HuO-3N1 MYPHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MWnJR|UxRTlwNkCxNFgh|ryP MnuwV2FPT0WU
BHT-101 MY\Hdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MYnJR|UxRTFzLkO4JO69VQ>? NHnMUY5USU6JRWK=
KYSE-150 MlTaS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NGG3fpNKSzVyPUGxMlU5PDFizszN MmjpV2FPT0WU
MC-IXC MlrxS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? M{fjeGlEPTB;MUKuNlI6OiEQvF2= NFX4fXRUSU6JRWK=
D-423MG NVT1b2FpT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= M1LJVWlEPTB;MUKuO|Y2PyEQvF2= NV31WXJPW0GQR1XS
NY NGjmV3FIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MmGxTWM2OD1zND64PVA{KM7:TR?= NFvnWlFUSU6JRWK=
HOS MX\Hdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NHzVNZlKSzVyPUG1MlY4OTlizszN MYPTRW5ITVJ?
NB7 MVXHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NH\ye41KSzVyPUG1Mlg6OSEQvF2= M3nwVnNCVkeHUh?=
DMS-273 MWjHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MYnJR|UxRTF4Lk[3NVMh|ryP NIjKS2VUSU6JRWK=
MDA-MB-361 NIHYW2ZIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MmPiTWM2OD1zNz6yO|EyKM7:TR?= MW\TRW5ITVJ?
DU-145 MnXGS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MV\JR|UxRTF6LkOyJO69VQ>? NV7rTppSW0GQR1XS
NCI-H82 M4PkNmdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 M2W0NWlEPTB;MUmuPFM5PiEQvF2= M3\JWXNCVkeHUh?=
NCI-SNU-1 M4PvOmdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MXjJR|UxRTJyLkCxPVYh|ryP NIfubXpUSU6JRWK=
GCT MX7Hdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NEDMVZdKSzVyPUKwMlg5OjRizszN NYXYO5lsW0GQR1XS
C2BBe1 M4XnSmdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NUDXZ3ZnUUN3ME2yNU4yODV6IN88US=> NYrGTFJVW0GQR1XS
LB2241-RCC M1HmR2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NYHSbYFnUUN3ME2yNU45PDRzIN88US=> MkXzV2FPT0WU
COLO-829 NIjBV3pIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MWTJR|UxRTJ{LkG4O|Eh|ryP MYfTRW5ITVJ?
EW-11 M3qyVWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 Mk\4TWM2OD1{Mj64NFIzKM7:TR?= MWjTRW5ITVJ?
NCI-H526 M164Nmdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 Ml7TTWM2OD1{Mz60O|E4KM7:TR?= NYLyVFdjW0GQR1XS
SF295 MlrCS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MlzWTWM2OD1{ND6wNlUzKM7:TR?= NHLCc4lUSU6JRWK=
D-566MG MkX6S5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MmHWTWM2OD1{NT6yPVQ{KM7:TR?= M2HrRXNCVkeHUh?=
8505C NYjlVpVVT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NYC0bnR1UUN3ME2yOU43OzNzIN88US=> M4K1PHNCVkeHUh?=
HT-29 NHrnc4VIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NWm5bWdvUUN3ME2yOk4xPDNzIN88US=> NHLCNW5USU6JRWK=
NBsusSR MXHHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? M{jUSGlEPTB;Mk[uPFAxPiEQvF2= NIjvXHNUSU6JRWK=
BV-173 NX3DNVFuT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NWjzTYxpUUN3ME2yPE4{OTh{IN88US=> Mk\MV2FPT0WU
CTB-1 MVXHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NX\6ZmV6UUN3ME2zNE4yODNzIN88US=> MX7TRW5ITVJ?
JAR NYXBblZkT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MmXGTWM2OD1|Mj61N|cyKM7:TR?= MkfjV2FPT0WU
CAMA-1 NGK3XYhIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MknnTWM2OD1|Mz60OlE2KM7:TR?= NVXIbGJ4W0GQR1XS
CAL-51 MofJS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? M4X3PWlEPTB;M{SuO|E4PiEQvF2= Ml;wV2FPT0WU
A172 Mnu4S5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? M{HmZ2lEPTB;M{euOFkzOSEQvF2= MmnsV2FPT0WU
QIMR-WIL M1vxUWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 M3jNb2lEPTB;M{iuNFcxQCEQvF2= MUjTRW5ITVJ?
AsPC-1 NETPdINIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MXzJR|UxRTN6LkS2OVEh|ryP MnvGV2FPT0WU
MKN7 MkS1S5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MYTJR|UxRTN7LkCwO|kh|ryP NHXZR5dUSU6JRWK=
ONS-76 M3zrdGdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 M4Ln[GlEPTB;NEOuN|A2PyEQvF2= MnXWV2FPT0WU
RS4-11 M1Hxc2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MVvJR|UxRTR2LkC3OVIh|ryP NGnzbGRUSU6JRWK=
NOS-1 M3\DVmdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MmnCTWM2OD12ND62NFMyKM7:TR?= NH\jTIdUSU6JRWK=
A101D Mn20S5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NYi2WFhCUUN3ME20OE45ODJ|IN88US=> Ml\IV2FPT0WU
HCC1806 M2HueWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MY\JR|UxRTR4LkGxOFgh|ryP MkDnV2FPT0WU
CAL-27 M2jueGdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 M4HEWmlEPTB;NEeuO|I1PiEQvF2= NWSwSY1KW0GQR1XS
BT-549 MXfHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MkC2TWM2OD12OD61N|E2KM7:TR?= NVPnWGprW0GQR1XS
LCLC-97TM1 MUTHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MlLPTWM2OD12OT6yOFE{KM7:TR?= M3zkNHNCVkeHUh?=
A4-Fuk MUTHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? M1XGUGlEPTB;NEmuPFQ6KM7:TR?= MWfTRW5ITVJ?
OVCAR-4 M4q4OWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NF[2UpBKSzVyPUWwMlA3ODFizszN M1K3TXNCVkeHUh?=
HD-MY-Z M{fzWmdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 M1jE[GlEPTB;NUCuO|c3PCEQvF2= MlTpV2FPT0WU
NCI-H292 NVPtPZVJT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= Mm\2TWM2OD13MD64O|U5KM7:TR?= NH\iToJUSU6JRWK=
Sk-ChA-1  NF\rb3pIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= M4jTOFAvOjYkgKO1NEDPxE1? NVjFR5gzPzJiaB?= MXrJR|UxRTd2LkW0xtEzNjV6zszN MlPvNlU4PDJ2OEK=
Mz-ChA-1 NVLN[Hg5T3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MUWwMlI26oDVNUCg{txO MVm3NkBp NH;mXZdKSzVyPUW0Mlk4yrF|LkS1{txO M1rofVI2PzR{NEiy
Smo-WT NGKwVW9Iem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MkDCTWM2OMLib3[gNVTDqG6P NF\Q[pozPDJ7MUGwOC=>
Smo-D473H  NGW0OGxIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NH7rW|BKSzVywrDv[kA4NjIEoN88US=> M3:1fVI1OjlzMUC0
K562 MUHGeY5kfGmxbjDBd5NigQ>? MXSxNEDPxE1? MYi3NkBp NG\jS5Zz\WS3Y3XzJJRp\SCneIDy[ZN{cW:wIH;mJGdtcTIEoB?= NGSwTokzOzNzOUiyOC=>
T315I BCR-ABL BaF3 NGfRe2tHfW6ldHnvckBCe3OjeR?= NFmxVIwyOCEQvF2= NIDjR|I4OiCq Mn[wdoVlfWOnczD0bIUh\XiycnXzd4lwdiCxZjDHcIkyyqB? M3\WOFI{OzF7OEK0
TF-1 BCR-ABL M{LMbmZ2dmO2aX;uJGF{e2G7 MUGxNEDPxE1? M37kdFczKGh? NGTzPItz\WS3Y3XzJJRp\SCneIDy[ZN{cW:wIH;mJGdtcTIEoB?= M3zVWVI{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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