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 NFP0R3pIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MULJR|UxRTBwMEeyOFgh|ryP M3HVfnNCVkeHUh?=
HCE-T NInPOYFIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MX;JR|UxRTFwM{KyOFch|ryP MkLPV2FPT0WU
D-542MG M3nWWmdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NHf5Z2tKSzVyPUGuPFY4OzdizszN M{D3NnNCVkeHUh?=
23132-87 M4\vc2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NIjXdllKSzVyPUSuOFAyPDdizszN NFnSVIhUSU6JRWK=
HDLM-2 M37n[mdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MVzJR|UxRThwMES3OlYh|ryP M2XHT3NCVkeHUh?=
ACN MVHHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? M3HFZ2lEPTB;OD61NFExQSEQvF2= MnLYV2FPT0WU
HuO-3N1 M{fMbGdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NHu1UJBKSzVyPUmuOlAyODhizszN NGTu[lNUSU6JRWK=
BHT-101 M{\6bWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MnvVTWM2OD1zMT6zPEDPxE1? MVvTRW5ITVJ?
KYSE-150 NXXlUlFET3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NIryfGZKSzVyPUGxMlU5PDFizszN NVWxVIE{W0GQR1XS
MC-IXC NE\3RVVIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NF;kN3ZKSzVyPUGyMlIzQTJizszN M1nMN3NCVkeHUh?=
D-423MG M1\Bcmdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MVHJR|UxRTF{Lke2OVch|ryP MnrMV2FPT0WU
NY MonSS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NWfiWGd6UUN3ME2xOE45QTB|IN88US=> MUHTRW5ITVJ?
HOS M4[0XWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 M1rkcWlEPTB;MUWuOlcyQSEQvF2= MWTTRW5ITVJ?
NB7 NF7ZO|hIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MYLJR|UxRTF3Lki5NUDPxE1? NF7Zb|hUSU6JRWK=
DMS-273 NGLaPVVIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NV7QWoVOUUN3ME2xOk43PzF|IN88US=> M2TP[nNCVkeHUh?=
MDA-MB-361 MYfHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MYLJR|UxRTF5LkK3NVEh|ryP NGnFUWpUSU6JRWK=
DU-145 M13x[Wdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MVTJR|UxRTF6LkOyJO69VQ>? MUnTRW5ITVJ?
NCI-H82 MUHHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? M{\qNWlEPTB;MUmuPFM5PiEQvF2= NYr3TXlQW0GQR1XS
NCI-SNU-1 MV3Hdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? M3G3S2lEPTB;MkCuNFE6PiEQvF2= NFnt[WZUSU6JRWK=
GCT NHjzUG1Iem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MkTYTWM2OD1{MD64PFI1KM7:TR?= NULJb4hXW0GQR1XS
C2BBe1 MkjhS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? M4nzSWlEPTB;MkGuNVA2QCEQvF2= MornV2FPT0WU
LB2241-RCC NFz2ZVdIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MUHJR|UxRTJzLki0OFEh|ryP NGjjVFdUSU6JRWK=
COLO-829 NV3M[o1kT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= M1v3V2lEPTB;MkKuNVg4OSEQvF2= M2W0UXNCVkeHUh?=
EW-11 NEW0S5FIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= M{nnc2lEPTB;MkKuPFAzOiEQvF2= NGrrcZdUSU6JRWK=
NCI-H526 M3rRXGdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MmXaTWM2OD1{Mz60O|E4KM7:TR?= M4fVc3NCVkeHUh?=
SF295 MVTHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NULmNWFMUUN3ME2yOE4xOjV{IN88US=> Mlv1V2FPT0WU
D-566MG MUPHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MWjJR|UxRTJ3LkK5OFMh|ryP MlSzV2FPT0WU
8505C MmjBS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MVzJR|UxRTJ3Lk[zN|Eh|ryP NWPxcHlyW0GQR1XS
HT-29 MkCyS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NFTuc5VKSzVyPUK2MlA1OzFizszN MV7TRW5ITVJ?
NBsusSR M1PpTGdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NVzV[Jo5UUN3ME2yOk45ODB4IN88US=> MYnTRW5ITVJ?
BV-173 NUDXSZBjT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NGnZ[nNKSzVyPUK4MlMyQDJizszN NV3RT|k6W0GQR1XS
CTB-1 MYDHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? M1PMU2lEPTB;M{CuNVA{OSEQvF2= MnrFV2FPT0WU
JAR MUPHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MXHJR|UxRTN{LkWzO|Eh|ryP NYDMfIJwW0GQR1XS
CAMA-1 M{K2d2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7 Mnf6TWM2OD1|Mz60OlE2KM7:TR?= MUjTRW5ITVJ?
CAL-51 MVvHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NFPFbHFKSzVyPUO0MlcyPzZizszN NGDWdIlUSU6JRWK=
A172 MnvzS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? Ml;oTWM2OD1|Nz60PVIyKM7:TR?= MoS5V2FPT0WU
QIMR-WIL M172fGdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MoDXTWM2OD1|OD6wO|A5KM7:TR?= NYD6Z5BRW0GQR1XS
AsPC-1 MnXjS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MU\JR|UxRTN6LkS2OVEh|ryP NYPQPJluW0GQR1XS
MKN7 M1v0OGdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NIr0d2lKSzVyPUO5MlAxPzlizszN NHH1fGhUSU6JRWK=
ONS-76 NVrDSWhiT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NUCyUoZ6UUN3ME20N{4{ODV5IN88US=> MnvMV2FPT0WU
RS4-11 NHXpeI1Iem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NVWwOo1WUUN3ME20OE4xPzV{IN88US=> NX30dnRZW0GQR1XS
NOS-1 MnfES5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MUTJR|UxRTR2Lk[wN|Eh|ryP NUK5XpZtW0GQR1XS
A101D MYnHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MW\JR|UxRTR2LkiwNlMh|ryP MXzTRW5ITVJ?
HCC1806 Mn3lS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NUCxeYRIUUN3ME20Ok4yOTR6IN88US=> MX7TRW5ITVJ?
CAL-27 NWnqVWlET3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= Ml:yTWM2OD12Nz63NlQ3KM7:TR?= NVXzOmxJW0GQR1XS
BT-549 NX\sVWJPT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NI\XU2FKSzVyPUS4MlU{OTVizszN MVHTRW5ITVJ?
LCLC-97TM1 NEDtRWlIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MmeyTWM2OD12OT6yOFE{KM7:TR?= MkHDV2FPT0WU
A4-Fuk MV7Hdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MmThTWM2OD12OT64OFkh|ryP M3zYO3NCVkeHUh?=
OVCAR-4 M2XBOWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NVO5foV5UUN3ME21NE4xPjBzIN88US=> MUXTRW5ITVJ?
HD-MY-Z Mn7SS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MnTYTWM2OD13MD63O|Y1KM7:TR?= MkT3V2FPT0WU
NCI-H292 NIjaXWRIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MnjsTWM2OD13MD64O|U5KM7:TR?= MlHTV2FPT0WU
Sk-ChA-1  NVnvN3ZNT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= M{fyXFAvOjYkgKO1NEDPxE1? NUjnRmlQPzJiaB?= MXjJR|UxRTd2LkW0xtEzNjV6zszN MUKyOVc1OjR6Mh?=
Mz-ChA-1 NVj2TnRMT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MX6wMlI26oDVNUCg{txO NIDCeWo4OiCq NY[2TmsyUUN3ME21OE46P8LzMz60Oe69VQ>? NFjycpUzPTd2MkS4Ni=>
Smo-WT MoT2S5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MX7JR|UxyqCxZjCxOOKhdk1? M3SyVFI1OjlzMUC0
Smo-D473H  NFvjS|BIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NXjmeoJsUUN3MNMgc4YhPy5zwrFOwG0> M1m3UVI1OjlzMUC0
K562 Ml;aSpVv[3Srb36gRZN{[Xl? M1r4flExKM7:TR?= NFfUS3A4OiCq Mn3MdoVlfWOnczD0bIUh\XiycnXzd4lwdiCxZjDHcIkyyqB? NILBZlgzOzNzOUiyOC=>
T315I BCR-ABL BaF3 M4HNRWZ2dmO2aX;uJGF{e2G7 MlvTNVAh|ryP M{fMRVczKGh? NVTZWoRqemWmdXPld{B1cGViZYjwdoV{e2mxbjDv[kBIdGlzwrC= NIfyU3gzOzNzOUiyOC=>
TF-1 BCR-ABL M3vLVGZ2dmO2aX;uJGF{e2G7 MYCxNEDPxE1? MlLWO|IhcA>? NUTZdVB2emWmdXPld{B1cGViZYjwdoV{e2mxbjDv[kBIdGlzwrC= Mk\VNlM{OTl6MkS=

... 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 (33)

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
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