Vismodegib (GDC-0449)

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。

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Vismodegib (GDC-0449) 化学構造
分子量: 421.3

品質と確認

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Quality Control & MSDS

製品情報

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製品の説明

生物活性

情報 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。
目標 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]
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

推薦された実験操作 (公開の文献だけ)

細胞アッセイ: [2]

細胞系 MDCKII cells
濃度 20 μM
処理時間 2 hours
方法 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
管理 Orally
Solubility 0.5% methylcellulose/0.2% Tween 80 30 mg/mL
* 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.

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

SpeciesBaboonDogMonkeyRabbitGuinea pigRatHamsterMouse
Weight (kg)121031.80.40.150.080.02
Body Surface Area (m2)0.60.50.240.150.050.0250.020.007
Km factor202012128653
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 DMSO
別名
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 0.5% methylcellulose/0.2% Tween 80 30 mg/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

研究分野

カスタマーレビュー (15)


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Rating
Source Gastroenterology, 2012, 143, 1319-29. Vismodegib (GDC-0449) purchased from Selleck
Method qRT-PCR/immunostaining
Cell Lines MF-HSCs
Concentrations 1 μM
Incubation Time 4 d
Results Conditional deletion of SMO in MF-HSCs recapitulated the effects of GDC-0449, causing significant down-regulation of glyco-lytic genes and MF genes.

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Rating
Source Gastroenterology, 2012, 143, 1319-29. Vismodegib (GDC-0449) purchased from Selleck
Method Immunohistochemistry
Cell Lines MDR2 -/- mice
Concentrations 1 μM
Incubation Time 4 d
Results We found that treating year-old MDR2 -/- mice with a 9-day course of GDC-0449 substantially reduced the numbers of PKM2-positive cells despite the ongoing genetic stimulus for liver repair.

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Source Gut, 2013, 62, 299-309. Vismodegib (GDC-0449) purchased from Selleck
Method Immunohistochemistry
Cell Lines Mdr2 -/- mice/hepatectomised mice
Concentrations
Incubation Time
Results Treatment of Mdr2 -/- mice with GDC-0449 (Hh signalling antagonist) significantly reduced the number of Gli2 and CD31 (a commonly used capillarisation marker in vivo) double-positive cells in the liver (figure A,B). Similar results were observed in partial hepatectomised mice treated with cyclopamine ( figure C).

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Source Hepatology, 2011, 54, 1580-90. Vismodegib (GDC-0449) purchased from Selleck
Method qRT-PCR/Western blot
Cell Lines Huh7.5 cells
Concentrations 0-5 μM
Incubation Time 72 h
Results GDC-0449, a preclinical Hh pathway inhibitor, inhibits replication of JFH1 HCV in a dose-response manner.

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Source Cancer Res, 2012, 72, 5912-20. Vismodegib (GDC-0449) purchased from Selleck
Method qRT-PCR/Western blot
Cell Lines HepG2/Huh7 cells
Concentrations 1 μmol/L
Incubation Time
Results GDC-0449 treatment of HepG2X cells decreased mRNA levels of Shh by 2.6-fold (61%, P < 0.005), PTCH1 by 6.8-fold (85%, P < 0.05), and Gli2 by 2.4-fold (58%, P < 0.05). GDC-0449 reduced Gli2 in HepG2X cells (2.2-fold; 55%, P < 0.02) and in Huh7X cells (3.8-fold; 74%, P < 0.02), but not in treated compared with untreated control cells (Fig. 1). GDC-0449 also reduced PTCH1 in HepG2X (1.8-fold; 44%, P < 0.02) and Huh7X cells (2.6-fold; 61%, P < 0.01), but not in the HBx negative cultures. Hence, HBx stimulates expression of Hhcomponents in human liver cancer cells.

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Rating
Source Cancer Res, 2013, 72, 5912-20. Vismodegib (GDC-0449) purchased from Selleck
Method Phenotypic assays
Cell Lines HBx positive/negative cells
Concentrations 1 μmol/L
Incubation Time
Results GDC-0449 decreased the clonability of Huh7X cells by 2.2-fold compared with untreated cells (P < 0.01), and of HepG2X cells by 1.8-fold compared with untreated cells.

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Rating
Source Cancer Res, 2014, 72, 5912-20. Vismodegib (GDC-0449) purchased from Selleck
Method Western blot/Immunohistochemistry
Cell Lines Twelve-month-old mice
Concentrations
Incubation Time
Results Untreated 12-month-old HBxTg had multiple tumors on the surface of their livers (Fig. A) although most GDC-0449-treated m ice had fewer tumors. These differences were statistically significant (Fig. B). Excised tumors showed lower levels of Gli2 in GDC- 0449-treated mice compared with controls(Fig. C).The latter was confirmed by staining , where no Gli2 was observed in treated compared with untreated mice (Fig . D).

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Source Chem Biol, 2012, 19, 972-82. Vismodegib (GDC-0449) purchased from Selleck
Method Hh Activity Assays
Cell Lines ShhLightII cells/SmoM2 cells
Concentrations 0-10 μM
Incubation Time 6 h
Results Hh pathway inhibition by GDC0449, Cyc and SANT-1, as measured by both Gliluciferase induction (Figure A) and Smo ciliary localization ( Figures B and C), was dramatically reduced in vitro in the presence of FA. Thus, FA cotreatment leads to a drug-dependent alteration of cellular response to chemical inhibitors of Smo. This may occur through competition, or the requirement for a higher level of GDC-0449 to inhibit Hh-driven pathway activity in the presence of GC, but the outcome resembles the genetic resistance seen with a dominant active Smo mutation SmoM2) (Figure A).

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Source Chem Biol, 2012, 19, 972-82. Vismodegib (GDC-0449) purchased from Selleck
Method Hh Activity Assays
Cell Lines Smo::EGFP/Iv s::tagRFPT cells
Concentrations 0-1000 nM
Incubation Time
Results Bud enhanced GDC0449’s activity to block Smo accumulation at the PC and Hh pathway inhibition.

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Source J Neurooncol , 2011, 105, 475-483. Vismodegib (GDC-0449) purchased from Selleck
Method Quantitative RT-PCR
Cell Lines Mouse medulloblastoma primary cells (U51669)
Concentrations 0-100 nM
Incubation Time
Results GDC-0449 effectively suppressed Gli1, which is a Shh pathway target gene.

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Rating
Source PLoS One, 2013, 8, e74141. Vismodegib (GDC-0449) purchased from Selleck
Method H&E staining, Western blot
Cell Lines C6
Concentrations 1-20 uM
Incubation Time 24 h
Results GDC-0449 inhibited the activation of Hh signaling in the irradiated livers.

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Rating
Source PLoS One, 2011, 6, e23943. Vismodegib (GDC-0449) purchased from Selleck
Method Immunohistochemistry/qRT-PCR
Cell Lines MDR2 -/- mice
Concentrations 40 mg/kg
Incubation Time 9 d
Results Overall survival between the two groups in the second cohort was equal, with no deaths in the DMSO treatment group and 1 death in the GDC-0449 treatment group secondary to iatrogenic injury. Both the liver parenchyma and tumors of treated mice showed decreased expression of the Hh pathway target Gli2 ( Figures A–B). Real-time PCR analysis of resected tumors revealed that GDC-0449 treatment released the inhibitory effects of Hh signaling on PPARa ˜ , causing a significant increase in its gene expression ( Figure C). Treatment with GDC-0449 also caused a significant decrease in expression of Gli1, another Hh target gene (Figure D ).

Click to enlarge
Rating
Source PLoS One, 2011, 6, e23943. Vismodegib (GDC-0449) purchased from Selleck
Method Immunohistochemistry
Cell Lines MDR2 -/- mice
Concentrations 40 mg/kg
Incubation Time 9 d
Results Treatment with GDC-0449 decreased α-sma-expressing myofibroblastic cells, hepatic expression of TGF- β andPDGF- β, Sirius red staining, and hydroxyproline content, demonstrating that Hh pathway inhibition reduced liver fibrosis.

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Rating
Source PLoS One, 2011, 6, e23943. Vismodegib (GDC-0449) purchased from Selleck
Method Immunohistochemistry/QRT-PCR analysis
Cell Lines MDR2 -/- mice
Concentrations 40 mg/kg
Incubation Time 9 d
Results Immunohistochemistry and quantitative morphometry demonstrated that inhibition of the Hh pathway with GDC-0449 significantly decreased osteopontin staining within primary liver tumors ( Figure A ). Similar treatment-related decreases in CD44 + tumor cells were also noted (Figure B). Gene expression analysis showed that expression of both osteopontin and CD44 mRNAs also tended to decrease in GDC-0449-treated mice ( Figure C ).

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Source Vismodegib (GDC-0449) purchased from Selleck
Method Flow cytometry
Cell Lines ABCG2-expressing cell sublines
Concentrations 50 µM
Incubation Time
Results We examined the inhibition of Pp-18 efflux to assess reported inhibitors of ABCG2-mediated drug resistance. The fold value is defined as the accumulation of Pp-18 in the presence of an inhibitor divided by the accumulation of Pp-18 in the absence of an inhibitor. vismodegib demonstrated a significant increase in Pp-18 accumulation in both human and mouse ABCG2-expressing cell lines.

製品表彰状 (26)

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