GDC-0879

GDC-0879 は新型有効の選択B-Raf阻害剤、精製のB-RafV600E酵素や細胞p-ERKを作用すると、IC50がそれぞれ0.13 nM と 63 nMとなる.

目録号S1104
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GDC-0879 化学構造
分子量: 334.37

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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 GDC-0879 は新型有効の選択B-Raf阻害剤、精製のB-RafV600E酵素や細胞p-ERKを作用すると、IC50がそれぞれ0.13 nM と 63 nMとなる.
目標 B-Raf
IC50 0.13 nM [1]
In vitro試験 GDC-0879 also inhibits cellular pERK with IC50 of 63 nM. GDC-0879 shows comparable potency in A375 melanoma and Colo205 colorectal carcinoma cell lines, both of which are B-RafV600E mutant, with IC50 of 59 nM and 29 nM for pMEK1 inhibition respectively. GDC-0879 potently inhibits B-RafV600E in Malme3M cells with IC50 of 0.75 μM. GDC-0879 also shows EC50 values < 0.5 μM in many tumor cells (A375, 624, SK-MEL-28, Malme3M, C32, 928, 888, G-361, Colo205, Colo206, SW1417, CL34, and Colo201). [1]
In vivo試験 In GDC-0879 treated mice, both cell line- and patient-derived BRAFV600E tumors exhibit stronger and more sustained pharmacodynamic inhibition (>90% for 8 hours) and improved survival compared to mutant KRAS-expressing tumors. Although there is involvement of activated RAF signaling in RAS-induced tumorigenesis, decreased time to progression is observed for some KRAS-mutant tumors following GDC-0879 administration. Whereas GDC-0879-mediated efficacy is associated strictly with B-RafV600E status, MEK inhibition also attenuates proliferation and tumor growth of cell lines expressing wild-type BRAF (81% KRAS mutant, 38% KRAS wild type). The responsiveness of B-RafV600E melanoma cells to GDC-0879 could be dramatically altered by pharmacologic and genetic modulation of PI3K pathway activity. [2]
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特集

推薦された実験操作 (公開の文献だけ)

動物実験: [2]

動物モデル Female nu/nu mice
製剤 0.5% methylcellulose/0.2% Tween 80
投薬量 100 mg/kg
管理 Oral gavage
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.
1

参考

化学情報

Download GDC-0879 SDF
分子量 334.37
化学式

C19H18N4O2

CAS No. 905281-76-7
保管 2年-20℃
6月-80℃in DMSO
別名
溶解度 (25°C) * In vitro DMSO 67 mg/mL (200 mM)
<1 mg/mL (<1 mM)
エタノール 5 mg/mL (14 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 (E)-5-(1-(2-hydroxyethyl)-3-(pyridin-4-yl)-1H-pyrazol-4-yl)-2,3-dihydroinden-1-one oxime

研究分野

カスタマーレビュー (4)


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Source J Natl Cancer Inst, 2012, 104(21), 1673-9. GDC-0879 purchased from Selleck
Method Western Blot
Cell Lines primary human melanocytes
Concentrations 1 uM
Incubation Time 18 h
Results Furthermore, in BRAFV600E melanoma cells, the highly selective BRAFV600E inhibitor GDC-0879 and three selective MEK inhibitors [PD184352/CI-1040, U0126, PD98059] did not suppress c-Jun levels, although they effectively reduced phospho-ERK levels.

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Source J Natl Cancer Inst, 2012, 104(21), 1673-9 . GDC-0879 purchased from Selleck
Method Xenograft
Cell Lines athymic nude Foxn1nu mice
Concentrations 3mg/kg
Incubation Time 13 day
Results CDK2/4 inhibition augmented statistically significant growth reduction of melanoma xenografts in vivo by the BRAF and MEK inhibitors (GDC-0879 and CI1040).

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Source Proc Natl Acad Sci USA , 2011, 108, 6067-6072. GDC-0879 purchased from Selleck
Method Western blotting
Cell Lines Cells overexpressing myc-CRAF and BRAF
Concentrations 10/50 µM
Incubation Time 1/2 h
Results GDC0879 but not PLX4720 induced BRAF/CRAF dimer formation (Fig. A). However, both GDC0879 and PLX4720 induced complexes between KSR1 and CRAF and enhanced interactions between KSR1 and BRAF (Fig. B and C), which suggested that KSR1/RAF complexes induced by the drug might explain the effects ofthe type I BRAF specific inhibitors. As reported previously, treatment of wild-type cells with either drug strongly induced ERK activation at low to intermediate doses but inhibited ERK activation at higher doses (Fig. D and E). Similar results were obtained with cells expressing constitutively active RAS (Fig. D and E) or after serum treatment. Strikingly, in KSR deficient cells, ERK activation was significantly attenuated after PLX4720 or GDC0879 treatment (Fig. D and E), which demonstrates that the ability of PLX4720 and GDC0879 to activate ERK requires the presence of KSR1. We found that, when KSR1 was overexpressed withCRAF, MEK activation was induced by PLX4720 or GDC0879 treatment (Fig. F). this result suggested that induction of the CRAF/KSR1 complex might be important in the activation of MEK. In vitro kinase activity toward MEK was detected but only after drug treatment (Fig. G), which suggests KSR1/CRAF complex formation kinase activity toward MEK.

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Source Dr. Jong-in Park from Medical College of Wisconsin. GDC-0879 purchased from Selleck
Method Western blotting
Cell Lines B-RafV600E mutated melanoma line
Concentrations 1-10 µM
Incubation Time 1/24 h
Results GDC-0879 treatment resulted in a reduction of MEK1/2 and ERK1/2 phosphorylation in A375 cell.

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