Background
IC50: 0.13 nM against purified B-Raf V600E enzyme; a cellular pERK IC50 of 63 nM in the MALME-3M cell line
GDC-0879 is synthsized as a potent and selective B-Raf inhibitor. The Raf/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase signaling pathway is reported to be involved in cellular responses, which is relevant to tumorigenesis.
In vitro: GDC-0879 is a B-Raf inhibitor against various in vitro and cell-based assays, such as A375 melanoma and Colo205 colorectal carcinoma cell lines, both of which are V600E B-Raf mutant. When screened against a panel of 140 kinases at its efficaciou dose, GDC-0879 showed expected activity only against C-Raf [1].
In vivo: In mice treated by GDC-0879, both cell line-and patient-derived BRAFV600E tumors exhibited stronger and more sustained pharmacodynamic inhibition (>90% for 8 hours) and improved survival compared with mutant KRAS-expressing tumors. Moreover, it was found that the responsiveness of BRAFV600E melanoma cells to GDC-0879 could be dramatically altered by pharmacologic and genetic modulation of phosphatidylinositol 3-kinase pathway activity [2].
Clinical trial: GDC-0879 is still in the preclinical development stage, and no clinical data are available currently.
参考文献:
[1] Wong H, Belvin M, Herter S, Hoeflich KP, Murray LJ, Wong L, Choo EF.? Pharmacodynamics of 2-[4-[(1E)-1-(hydroxyimino)-2,3-dihydro-1H-inden-5-yl]-3-(pyridine-4-yl)-1H-pyrazol-1-yl]ethan-1-ol (GDC-0879), a potent and selective B-Raf kinase inhibitor: understanding relationships between systemic concentrations, phosphorylated mitogen-activated protein kinase kinase 1 inhibition, and efficacy. J Pharmacol Exp Ther. 2009 Apr;329(1):360-7.
[2] Hoeflich KP, Herter S, Tien J, Wong L, Berry L, Chan J, O'Brien C, Modrusan Z, Seshagiri S, Lackner M, Stern H, Choo E, Murray L, Friedman LS, Belvin M.? Antitumor efficacy of the novel RAF inhibitor GDC-0879 is predicted by BRAFV600E mutational status and sustained extracellular signal-regulated kinase/mitogen-activated protein kinase pathway suppression. Cancer Res. 2009 Apr 1;69(7):3042-51.
Protocol
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Cell experiment[1]:
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Cell lines
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Human melanoma A375 cells
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Preparation method
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The solubility of this compound in DMSO is > 10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37 ℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months.
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Reacting condition
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24 h, 10 μM
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Applications
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GDC-0879 is a potent, selective and orally bioavailable RAF small-molecule inhibitor. GDC-0879 effectively inhibited phospho-ERK with an IC50 value of 63 nmol/L and inhibited cellular viability of BRAF-mutant Malme3M cells with an EC50 value of 0.75 μmol/L. Moreover, there was a strong correlation between activating mutations of the BRAF oncogene and GDC-0879 sensitivity.
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Animal experiment [2]:
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Animal models
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Tumor xenograft female athymic nu/nu mice
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Dosage form
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Oral administration, 15, 25, 50, 100, and 200 mg/kg
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Application
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GDC-0879 inhibited tumor growth in A375 xenograft tumor-bearing mice in a dose-dependent manner and inhibited phosphorylation of MEK1 in A375 xenografts in a concentration-dependent manner with IC50 value of 3.06 μM.
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Other notes
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Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.
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参考文献:
[1]. Hoeflich K P, Herter S, Tien J, et al. Antitumor efficacy of the novel RAF inhibitor GDC-0879 is predicted by BRAFV600E mutational status and sustained extracellular signal-regulated kinase/mitogen-activated protein kinase pathway suppression[J]. Cancer research, 2009, 69(7): 3042-3051.
[2]. Wong H, Belvin M, Herter S, et al. Pharmacodynamics of 2-{4-[(1E)-1-(hydroxyimino)-2, 3-dihydro-1H-inden-5-yl]-3-(pyridine-4-yl)-1H-pyrazol-1-yl} ethan-1-ol (GDC-0879), a potent and selective B-Raf kinase inhibitor: understanding Relationships between systemic concentrations, phosphorylated mitogen-activated protein kinase kinase 1 inhibition, and efficacy[J]. Journal of Pharmacology and Experimental Therapeutics, 2009, 329(1): 360-367.
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