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 MX7Hdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NH25R2RKSzVyPUCuNFczPDhizszN MmfSV2FPT0WU
HCE-T M1u0e2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MmrQTWM2OD1zLkOyNlQ4KM7:TR?= M3fEV3NCVkeHUh?=
D-542MG MUPHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? Ml;PTWM2OD1zLki2O|M4KM7:TR?= M1LyXHNCVkeHUh?=
23132-87 M3P2N2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MnjCTWM2OD12LkSwNVQ4KM7:TR?= MWnTRW5ITVJ?
HDLM-2 MlvDS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? M1i4OWlEPTB;OD6wOFc3PiEQvF2= NH3JfXBUSU6JRWK=
ACN MmnUS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MnGzTWM2OD16LkWwNVA6KM7:TR?= MmjDV2FPT0WU
HuO-3N1 NYjTOGxwT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NX;Ub3l2UUN3ME25MlYxOTB6IN88US=> MXTTRW5ITVJ?
BHT-101 MY\Hdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NX[5V4dyUUN3ME2xNU4{QCEQvF2= Mln2V2FPT0WU
KYSE-150 M2[5eGdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MYHJR|UxRTFzLkW4OFEh|ryP M33je3NCVkeHUh?=
MC-IXC MVrHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? Mn3mTWM2OD1zMj6yNlkzKM7:TR?= MlfCV2FPT0WU
D-423MG MkfTS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? M3;rUWlEPTB;MUKuO|Y2PyEQvF2= M1PRVnNCVkeHUh?=
NY NWrhPWRFT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= M1rjT2lEPTB;MUSuPFkxOyEQvF2= M1zXcHNCVkeHUh?=
HOS NYH3ZYIyT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MmDOTWM2OD1zNT62O|E6KM7:TR?= MoiwV2FPT0WU
NB7 M1T2cGdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NVXnTGlXUUN3ME2xOU45QTFizszN M4r5enNCVkeHUh?=
DMS-273 NXz5U4xxT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= M3fvRWlEPTB;MU[uOlcyOyEQvF2= NXziUW9[W0GQR1XS
MDA-MB-361 NGjYeWVIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= M2r5cmlEPTB;MUeuNlcyOSEQvF2= MmXJV2FPT0WU
DU-145 MoLWS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MoPBTWM2OD1zOD6zNkDPxE1? M33Ud3NCVkeHUh?=
NCI-H82 MknuS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NIfuXFFKSzVyPUG5Mlg{QDZizszN MV3TRW5ITVJ?
NCI-SNU-1 M2\Rcmdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NETRflJKSzVyPUKwMlAyQTZizszN NILhW2JUSU6JRWK=
GCT MXnHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MmX4TWM2OD1{MD64PFI1KM7:TR?= M33MSnNCVkeHUh?=
C2BBe1 NW\3XZBST3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NX3j[lZOUUN3ME2yNU4yODV6IN88US=> MX3TRW5ITVJ?
LB2241-RCC MWrHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? M33NVGlEPTB;MkGuPFQ1OSEQvF2= MlHGV2FPT0WU
COLO-829 MlKxS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MnKzTWM2OD1{Mj6xPFcyKM7:TR?= Ml:0V2FPT0WU
EW-11 M1TXd2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NV;zOnhXUUN3ME2yNk45ODJ{IN88US=> M2TYenNCVkeHUh?=
NCI-H526 MnnRS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? Ml;ZTWM2OD1{Mz60O|E4KM7:TR?= NHLodVdUSU6JRWK=
SF295 MnzFS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NY\CO3ExUUN3ME2yOE4xOjV{IN88US=> NVnwbo15W0GQR1XS
D-566MG NX6xOodKT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NVfwT2RlUUN3ME2yOU4zQTR|IN88US=> NW\jUYkxW0GQR1XS
8505C MmrvS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NXLqNnNSUUN3ME2yOU43OzNzIN88US=> NH;sZ2ZUSU6JRWK=
HT-29 NWfoNlMzT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NUjCU4VJUUN3ME2yOk4xPDNzIN88US=> NYO0XVdNW0GQR1XS
NBsusSR MWHHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MknCTWM2OD1{Nj64NFA3KM7:TR?= NF:zRoZUSU6JRWK=
BV-173 MnKxS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NV\xdmp2UUN3ME2yPE4{OTh{IN88US=> NWHjTZlqW0GQR1XS
CTB-1 M4rabWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 M1rIdmlEPTB;M{CuNVA{OSEQvF2= MVjTRW5ITVJ?
JAR NV[1WVNGT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= M2C2bGlEPTB;M{KuOVM4OSEQvF2= NGfDRYNUSU6JRWK=
CAMA-1 MlPJS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MlmzTWM2OD1|Mz60OlE2KM7:TR?= NX;PZYp2W0GQR1XS
CAL-51 NVrkeYRjT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NVHiNnhqUUN3ME2zOE44OTd4IN88US=> MXzTRW5ITVJ?
A172 NEHxS4FIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= M3\K[mlEPTB;M{euOFkzOSEQvF2= M2XEcHNCVkeHUh?=
QIMR-WIL M2HuXGdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NIHVW49KSzVyPUO4MlA4ODhizszN Mo\sV2FPT0WU
AsPC-1 NWfMb3NoT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NIHzZ29KSzVyPUO4MlQ3PTFizszN MYDTRW5ITVJ?
MKN7 MUHHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NHXvTYdKSzVyPUO5MlAxPzlizszN NYDqW2RtW0GQR1XS
ONS-76 M{PXO2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NHuySJVKSzVyPUSzMlMxPTdizszN M3eyWHNCVkeHUh?=
RS4-11 MX7Hdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NFvpWnBKSzVyPUS0MlA4PTJizszN M2TpeXNCVkeHUh?=
NOS-1 MnvvS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NG[5S2lKSzVyPUS0MlYxOzFizszN MknQV2FPT0WU
A101D NVvPeIdZT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NYjnd2xwUUN3ME20OE45ODJ|IN88US=> NUH2XYNPW0GQR1XS
HCC1806 NFjYSlJIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NFzaU3FKSzVyPUS2MlEyPDhizszN MmnCV2FPT0WU
CAL-27 M{PKeWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MUPJR|UxRTR5LkeyOFYh|ryP NUjze5lWW0GQR1XS
BT-549 Mn[5S5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NV2zXlJFUUN3ME20PE42OzF3IN88US=> MojWV2FPT0WU
LCLC-97TM1 M37LPWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NGnXe2dKSzVyPUS5MlI1OTNizszN MUnTRW5ITVJ?
A4-Fuk NUDEdlNQT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= Mk\yTWM2OD12OT64OFkh|ryP M3nZNXNCVkeHUh?=
OVCAR-4 Mn7HS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? M1u1SWlEPTB;NUCuNFYxOSEQvF2= M1P0dXNCVkeHUh?=
HD-MY-Z MYjHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NIG0Zm1KSzVyPUWwMlc4PjRizszN NIfMZ|FUSU6JRWK=
NCI-H292 NXP6TYM4T3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MWPJR|UxRTVyLki3OVgh|ryP Ml;WV2FPT0WU
Sk-ChA-1  MmHxS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NFHId5IxNjJ34pETOVAh|ryP MlLrO|IhcA>? MlLKTWM2OD15ND61OOKyOi53ON88US=> MYSyOVc1OjR6Mh?=
Mz-ChA-1 MkfrS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? M4LTPVAvOjYkgKO1NEDPxE1? Ml;jO|IhcA>? Mnz2TWM2OD13ND65O:KyOy52Nd88US=> MYiyOVc1OjR6Mh?=
Smo-WT M3n5U2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NWnrN21FUUN3MNMgc4YhOTUEoH7N MVSyOFI6OTFyNB?=
Smo-D473H  NV7uR|A6T3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= M1nXd2lEPTEEoH;mJFcvOcLizszN MWGyOFI6OTFyNB?=
K562 MVnGeY5kfGmxbjDBd5NigQ>? M13Z[FExKM7:TR?= M{\Ke|czKGh? MXjy[YR2[2W|IITo[UBmgHC{ZYPzbY9vKG:oIFfsbVHDqA>? NETMR|czOzNzOUiyOC=>
T315I BCR-ABL BaF3 Mn\1SpVv[3Srb36gRZN{[Xl? M3rZVFExKM7:TR?= Mn\XO|IhcA>? MlnydoVlfWOnczD0bIUh\XiycnXzd4lwdiCxZjDHcIkyyqB? NYi3U|l3OjN|MUm4NlQ>
TF-1 BCR-ABL MYPGeY5kfGmxbjDBd5NigQ>? M13NZ|ExKM7:TR?= M1\sUFczKGh? MXTy[YR2[2W|IITo[UBmgHC{ZYPzbY9vKG:oIFfsbVHDqA>? MV2yN|MyQTh{NB?=

... 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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