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 NX\CW3hoT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NF;4XlJKSzVyPUCuNFczPDhizszN MX3TRW5ITVJ?
HCE-T NVHtV45HT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= Mmj2TWM2OD1zLkOyNlQ4KM7:TR?= M4rheHNCVkeHUh?=
D-542MG M1LZRWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NIL0XJJKSzVyPUGuPFY4OzdizszN MX\TRW5ITVJ?
23132-87 NUfVcnlXT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NXH4bnNCUUN3ME20MlQxOTR5IN88US=> MX3TRW5ITVJ?
HDLM-2 MlzhS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? M2qyPWlEPTB;OD6wOFc3PiEQvF2= NWDVN|J{W0GQR1XS
ACN Ml33S5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MXTJR|UxRThwNUCxNFkh|ryP NIDQeVRUSU6JRWK=
HuO-3N1 NVL1UHFoT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NUG1[GlQUUN3ME25MlYxOTB6IN88US=> M1PsXnNCVkeHUh?=
BHT-101 NW\oWZMxT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NFfnbZpKSzVyPUGxMlM5KM7:TR?= NHKy[|RUSU6JRWK=
KYSE-150 Mm\4S5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NELOWYZKSzVyPUGxMlU5PDFizszN NF3tWHZUSU6JRWK=
MC-IXC NH75b4pIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= M2nBRWlEPTB;MUKuNlI6OiEQvF2= M{OyfHNCVkeHUh?=
D-423MG MYnHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NXXaSJJYUUN3ME2xNk44PjV5IN88US=> M3\tVHNCVkeHUh?=
NY Ml\RS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NYntbZF6UUN3ME2xOE45QTB|IN88US=> NIrFbYJUSU6JRWK=
HOS MVHHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? M3TPZmlEPTB;MUWuOlcyQSEQvF2= Mnz3V2FPT0WU
NB7 NWrhclRUT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NIS3NVdKSzVyPUG1Mlg6OSEQvF2= NYLGc4tlW0GQR1XS
DMS-273 M4rGZWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NHXyTYlKSzVyPUG2MlY4OTNizszN NVnS[ow6W0GQR1XS
MDA-MB-361 NYDjWJh[T3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MoXMTWM2OD1zNz6yO|EyKM7:TR?= NIG1b5VUSU6JRWK=
DU-145 NIDTPYZIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= M325RmlEPTB;MUiuN|Ih|ryP NITlXpVUSU6JRWK=
NCI-H82 NVHaVGtxT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= M2W3XWlEPTB;MUmuPFM5PiEQvF2= NYjobZpbW0GQR1XS
NCI-SNU-1 MYnHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? Ml7PTWM2OD1{MD6wNVk3KM7:TR?= NFjx[YpUSU6JRWK=
GCT NWfuVHZtT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MnWzTWM2OD1{MD64PFI1KM7:TR?= NILReYpUSU6JRWK=
C2BBe1 NU\z[W1kT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MXnJR|UxRTJzLkGwOVgh|ryP MmDxV2FPT0WU
LB2241-RCC M4XESGdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NV[1OlhzUUN3ME2yNU45PDRzIN88US=> MYXTRW5ITVJ?
COLO-829 NGHGOJNIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= M{\RXmlEPTB;MkKuNVg4OSEQvF2= M124UnNCVkeHUh?=
EW-11 M1TF[Gdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MXfJR|UxRTJ{LkiwNlIh|ryP MoXqV2FPT0WU
NCI-H526 NGXm[pVIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MnfDTWM2OD1{Mz60O|E4KM7:TR?= MlfxV2FPT0WU
SF295 MkTrS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NGfMdpRKSzVyPUK0MlAzPTJizszN MXXTRW5ITVJ?
D-566MG MnP5S5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? M{T5TGlEPTB;MkWuNlk1OyEQvF2= NGDLXlVUSU6JRWK=
8505C M1XX[mdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MmjETWM2OD1{NT62N|MyKM7:TR?= M1:xcHNCVkeHUh?=
HT-29 NEnNT4ZIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= M3GxT2lEPTB;Mk[uNFQ{OSEQvF2= NGX5[ZNUSU6JRWK=
NBsusSR M3TWV2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MWfJR|UxRTJ4LkiwNFYh|ryP M2LleHNCVkeHUh?=
BV-173 M3nmW2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NX\Y[W05UUN3ME2yPE4{OTh{IN88US=> MYLTRW5ITVJ?
CTB-1 NFv6UW5Iem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NXG4b2EyUUN3ME2zNE4yODNzIN88US=> MV3TRW5ITVJ?
JAR NXO3UXBmT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NXHJOYhWUUN3ME2zNk42OzdzIN88US=> NHLIPWFUSU6JRWK=
CAMA-1 NUTPWGdZT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MV7JR|UxRTN|LkS2NVUh|ryP NFXBcXFUSU6JRWK=
CAL-51 MYHHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MkLUTWM2OD1|ND63NVc3KM7:TR?= NUC1Roh2W0GQR1XS
A172 NVnodpdkT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MlTpTWM2OD1|Nz60PVIyKM7:TR?= M{TtbnNCVkeHUh?=
QIMR-WIL NHfGXWxIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MmHWTWM2OD1|OD6wO|A5KM7:TR?= NGCye4RUSU6JRWK=
AsPC-1 M4\sfmdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 M2G1TmlEPTB;M{iuOFY2OSEQvF2= NWHTRWtZW0GQR1XS
MKN7 M4XsOGdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 M4\JXmlEPTB;M{muNFA4QSEQvF2= MUjTRW5ITVJ?
ONS-76 M{GyTWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 M{m0cWlEPTB;NEOuN|A2PyEQvF2= MYjTRW5ITVJ?
RS4-11 NVj2XlJUT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NVnUT4M4UUN3ME20OE4xPzV{IN88US=> MlfYV2FPT0WU
NOS-1 MWjHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MUPJR|UxRTR2Lk[wN|Eh|ryP M1HDTXNCVkeHUh?=
A101D MorzS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? M4nzfGlEPTB;NESuPFAzOyEQvF2= MYXTRW5ITVJ?
HCC1806 M{LWdWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NUXXepIyUUN3ME20Ok4yOTR6IN88US=> M1\POXNCVkeHUh?=
CAL-27 M{\MU2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7 M4DuVWlEPTB;NEeuO|I1PiEQvF2= MoWwV2FPT0WU
BT-549 M2HrRmdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MWDJR|UxRTR6LkWzNVUh|ryP MoO1V2FPT0WU
LCLC-97TM1 MmHLS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MXvJR|UxRTR7LkK0NVMh|ryP MVvTRW5ITVJ?
A4-Fuk MVPHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NYntb4FXUUN3ME20PU45PDlizszN NYHaRY15W0GQR1XS
OVCAR-4 M1fJUGdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 M2T3PWlEPTB;NUCuNFYxOSEQvF2= NEjtcJhUSU6JRWK=
HD-MY-Z NWfaXWt{T3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NUP2TXB2UUN3ME21NE44PzZ2IN88US=> M3ju[nNCVkeHUh?=
NCI-H292 NIjkW3VIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= Mn\4TWM2OD13MD64O|U5KM7:TR?= NXuyb21RW0GQR1XS
Sk-ChA-1  M3TucWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MVuwMlI26oDVNUCg{txO NHT0ZpE4OiCq Ml3sTWM2OD15ND61OOKyOi53ON88US=> M2H5VFI2PzR{NEiy
Mz-ChA-1 M3LrNGdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 M2DIelAvOjYkgKO1NEDPxE1? MmDhO|IhcA>? MmDKTWM2OD13ND65O:KyOy52Nd88US=> M3HFcFI2PzR{NEiy
Smo-WT MlS4S5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MYrJR|UxyqCxZjCxOOKhdk1? MYWyOFI6OTFyNB?=
Smo-D473H  Mnu3S5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? M3Oz[GlEPTEEoH;mJFcvOcLizszN MUCyOFI6OTFyNB?=
K562 NWLWe4JGTnWwY4Tpc44hSXO|YYm= NGLuW4oyOCEQvF2= NVf2U5lIPzJiaB?= NEfXSoFz\WS3Y3XzJJRp\SCneIDy[ZN{cW:wIH;mJGdtcTIEoB?= M1fMN|I{OzF7OEK0
T315I BCR-ABL BaF3 MkLVSpVv[3Srb36gRZN{[Xl? MmrrNVAh|ryP NIfZe4g4OiCq NY\QNXZ5emWmdXPld{B1cGViZYjwdoV{e2mxbjDv[kBIdGlzwrC= MlPaNlM{OTl6MkS=
TF-1 BCR-ABL Mn;QSpVv[3Srb36gRZN{[Xl? MU[xNEDPxE1? MnnRO|IhcA>? M{G5ZZJm\HWlZYOgeIhmKGW6cILld5Nqd25ib3[gS4xqOcLi NILON|kzOzNzOUiyOC=>

... 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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