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 M4DLcWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MkH2TWM2OD1yLkC3NlQ5KM7:TR?= NY\GeY9QW0GQR1XS
HCE-T M1\qS2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7 Ml3pTWM2OD1zLkOyNlQ4KM7:TR?= MXfTRW5ITVJ?
D-542MG MUnHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? M{C3XGlEPTB;MT64Olc{PyEQvF2= NYPWcJd5W0GQR1XS
23132-87 NWexeplVT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NX\PeWx5UUN3ME20MlQxOTR5IN88US=> MYnTRW5ITVJ?
HDLM-2 M3PrRmdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NUOybmVwUUN3ME24MlA1PzZ4IN88US=> MV;TRW5ITVJ?
ACN MkTSS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? M36xTmlEPTB;OD61NFExQSEQvF2= M3PNXXNCVkeHUh?=
HuO-3N1 NEfCZZRIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= M1LZdmlEPTB;OT62NFExQCEQvF2= M1O5Z3NCVkeHUh?=
BHT-101 MmPVS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NHnsb3BKSzVyPUGxMlM5KM7:TR?= M4jqR3NCVkeHUh?=
KYSE-150 M3zzXWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MYfJR|UxRTFzLkW4OFEh|ryP NWXZN2x2W0GQR1XS
MC-IXC Mkj4S5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MnXKTWM2OD1zMj6yNlkzKM7:TR?= MkTtV2FPT0WU
D-423MG NV7kNlFjT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= M{HjR2lEPTB;MUKuO|Y2PyEQvF2= MXHTRW5ITVJ?
NY MWTHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MnHXTWM2OD1zND64PVA{KM7:TR?= M2LKSHNCVkeHUh?=
HOS M2PXcWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MY\JR|UxRTF3Lk[3NVkh|ryP NILsW|JUSU6JRWK=
NB7 M2rJWWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MYnJR|UxRTF3Lki5NUDPxE1? M335fXNCVkeHUh?=
DMS-273 NUXxNlljT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= M3vKW2lEPTB;MU[uOlcyOyEQvF2= NGrzbphUSU6JRWK=
MDA-MB-361 MYTHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MnTXTWM2OD1zNz6yO|EyKM7:TR?= MkPhV2FPT0WU
DU-145 M2XkNGdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 M4DnRWlEPTB;MUiuN|Ih|ryP NHH1SlVUSU6JRWK=
NCI-H82 M3ftOGdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NX;HVJJ1UUN3ME2xPU45Ozh4IN88US=> Mo\CV2FPT0WU
NCI-SNU-1 Mn2wS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NH7zRmVKSzVyPUKwMlAyQTZizszN NHyyenVUSU6JRWK=
GCT M2fUVGdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MXfJR|UxRTJyLki4NlQh|ryP MX;TRW5ITVJ?
C2BBe1 NYP6XZhZT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= M1HoTGlEPTB;MkGuNVA2QCEQvF2= M{XBcnNCVkeHUh?=
LB2241-RCC NF\qdW1Iem:5dHigTY5pcWKrdHnvckBCe3OjeR?= M1jyXGlEPTB;MkGuPFQ1OSEQvF2= MVzTRW5ITVJ?
COLO-829 NHHKUJdIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NFK3ZoVKSzVyPUKyMlE5PzFizszN NVrhNmNYW0GQR1XS
EW-11 NV[yXZdqT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NHvBcHNKSzVyPUKyMlgxOjJizszN NHPiNlBUSU6JRWK=
NCI-H526 MULHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NXu5WpM4UUN3ME2yN{41PzF5IN88US=> NVy2dIh5W0GQR1XS
SF295 NWntbYJvT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MWTJR|UxRTJ2LkCyOVIh|ryP MVvTRW5ITVJ?
D-566MG NUP3WY5oT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MUDJR|UxRTJ3LkK5OFMh|ryP NYrSOHpMW0GQR1XS
8505C M3fzSWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MVTJR|UxRTJ3Lk[zN|Eh|ryP MonVV2FPT0WU
HT-29 MVLHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MnHsTWM2OD1{Nj6wOFMyKM7:TR?= NGD6TZFUSU6JRWK=
NBsusSR M4PUT2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7 Mmj3TWM2OD1{Nj64NFA3KM7:TR?= NIXxXJFUSU6JRWK=
BV-173 M{[zcWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 M1rNWmlEPTB;MkiuN|E5OiEQvF2= NUm0c|luW0GQR1XS
CTB-1 NXHYW5hZT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MYDJR|UxRTNyLkGwN|Eh|ryP NWPCVJFQW0GQR1XS
JAR MknjS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MYrJR|UxRTN{LkWzO|Eh|ryP M3;rZ3NCVkeHUh?=
CAMA-1 MWrHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? M362N2lEPTB;M{OuOFYyPSEQvF2= NWHGVllDW0GQR1XS
CAL-51 M1X0TWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MYDJR|UxRTN2LkexO|Yh|ryP NF32N5VUSU6JRWK=
A172 M2DXNGdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 M4G5eGlEPTB;M{euOFkzOSEQvF2= M3f6VXNCVkeHUh?=
QIMR-WIL MoXUS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MWrJR|UxRTN6LkC3NFgh|ryP NGexO4tUSU6JRWK=
AsPC-1 M2jpc2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NGrL[YRKSzVyPUO4MlQ3PTFizszN NF3B[nVUSU6JRWK=
MKN7 M2LRemdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MVvJR|UxRTN7LkCwO|kh|ryP NE\Db2hUSU6JRWK=
ONS-76 MYHHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NIP3WXBKSzVyPUSzMlMxPTdizszN NUG3O4tlW0GQR1XS
RS4-11 MkXpS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MlzFTWM2OD12ND6wO|UzKM7:TR?= M37ocXNCVkeHUh?=
NOS-1 NXnXeXllT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MlrZTWM2OD12ND62NFMyKM7:TR?= NFjxfYNUSU6JRWK=
A101D M1TuXGdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 M1rKXmlEPTB;NESuPFAzOyEQvF2= MVjTRW5ITVJ?
HCC1806 M{XsRmdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MWHJR|UxRTR4LkGxOFgh|ryP M2PZc3NCVkeHUh?=
CAL-27 NUX4doN[T3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NWTYO3V7UUN3ME20O{44OjR4IN88US=> MXfTRW5ITVJ?
BT-549 MVzHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? M2n1UWlEPTB;NEiuOVMyPSEQvF2= MlT5V2FPT0WU
LCLC-97TM1 NHnCVXFIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MlfCTWM2OD12OT6yOFE{KM7:TR?= M3L2R3NCVkeHUh?=
A4-Fuk M2fBfGdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MW\JR|UxRTR7Lki0PUDPxE1? M4SxZXNCVkeHUh?=
OVCAR-4 NVfxUWcyT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NF3qVXFKSzVyPUWwMlA3ODFizszN NVvXZYM2W0GQR1XS
HD-MY-Z MVvHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MnnSTWM2OD13MD63O|Y1KM7:TR?= NGHOe4RUSU6JRWK=
NCI-H292 MXTHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MYjJR|UxRTVyLki3OVgh|ryP NYDBUGV3W0GQR1XS
Sk-ChA-1  NHnjcFVIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NHvFbHcxNjJ34pETOVAh|ryP M3m3blczKGh? M2TZXWlEPTB;N{SuOVTDuTJwNUlOwG0> MUSyOVc1OjR6Mh?=
Mz-ChA-1 MYfHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MlHONE4zPeLCk{WwJO69VQ>? MnPuO|IhcA>? MmC5TWM2OD13ND65O:KyOy52Nd88US=> M3fVXVI2PzR{NEiy
Smo-WT NYGzTIdST3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NHnFXmtKSzVywrDv[kAyPMLibl2= NF7TcXIzPDJ7MUGwOC=>
Smo-D473H  NIrEOHpIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NEPHdplKSzVywrDv[kA4NjIEoN88US=> MXeyOFI6OTFyNB?=
K562 NX7j[4dKTnWwY4Tpc44hSXO|YYm= MlTnNVAh|ryP MXK3NkBp MWjy[YR2[2W|IITo[UBmgHC{ZYPzbY9vKG:oIFfsbVHDqA>? NH3jTYIzOzNzOUiyOC=>
T315I BCR-ABL BaF3 M1myUGZ2dmO2aX;uJGF{e2G7 NX\WfHE4OTBizszN NUjyfFBLPzJiaB?= NETPVWVz\WS3Y3XzJJRp\SCneIDy[ZN{cW:wIH;mJGdtcTIEoB?= NXrJZndyOjN|MUm4NlQ>
TF-1 BCR-ABL NWXicFVrTnWwY4Tpc44hSXO|YYm= Mo\1NVAh|ryP M4r4ZVczKGh? M1HtdZJm\HWlZYOgeIhmKGW6cILld5Nqd25ib3[gS4xqOcLi NXPsfFB1OjN|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 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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