GDC-0879 is a potent and selective B-Raf kinase inhibitor with an EC50 of 0.75 µM. GDC-0879 has been used in various research studies for its anti-cancer properties. In GDC-0879-treated mice, 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.
|Source||Mol Cancer Ther (2016). Figure 2. GDC-0879|
|Cell Lines||BRAF WT, NRAS-mutant BRO melanoma cells|
|Concentrations||100, 1000, 10000 nmol/L|
|Incubation Time||24 h|
|Results||In contrast, the tool compound GDC-0879 clearly induced formation of both CRAF/ARAF as well as CRAF/BRAF dimers. Nevertheless, BI 882370 induced phosphorylation of MEK1/2 and enhanced phosphorylation of ERK1/2 in BRO cells at concentrations between 3 and 300 nmol/L; importantly, however, expression of cyclins D1/D2 or Kip1/p27 was not affected|
|Cell lines||A375 and Colo205 cells|
|Preparation method||GDC-0879 in vitro IC50 estimates for pMEK inhibition were determined using A375 and Colo205 cells. In brief, A375 or Colo205 cells were incubated with a range of GDC-0879 concentrations (from 0.5 nM to 6.75 μM) for 25 min. Cells were lysed, and the lysates were subjected to centrifugation at 16,100g for 30 min, and the level of total protein was determined using the Bradford method (Bradford, 1976). Enzyme-linked immunosorbent assay kits were used to determine pMEK1 and total MEK1 protein levels in a 96-well format (Tago Biosource International, Camarillo, CA). Samples were analyzed in duplicate at 20 μg of protein per well according to the protocol of the supplier. The optical densities obtained at 450 nm were converted to units per milliliter (for pMEK1) or nanograms per milliliter (for total MEK1) using a standard curve determined with recombinant pMEK1 or MEK1. The pMEK1/total MEK1 ratios were then calculated as units per nanogram. The IC50 estimates for pMEK1 inhibition were estimated by nonlinear regression using GraphPad Prism version 4.02 (GraphPad Software Inc., San Diego, CA).|
|Concentrations||0.5 nM to 6.75 μM|
|Incubation time||25 min|
|Animal models||A375 and Colo205 tumor xenograft model|
|Formulation||0.5% methylcellulose/0.2% Tween-80 (MCT)|
|Dosages||A375 xenograft: 50, 100, 200mg/kg once daily / Colo205 xenograft:50, 100 mg/kg once daily|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|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.
Validation and application of a liquid chromatography-tandem mass spectrometric method for the determination of GDC-0879 and its metabolite in dog plasma using solid phase extraction.
Chou et al. J Pharm Biomed Anal. 2012 Nov;70:354-61. PMID: 22717139.
Disposition of GDC-0879, a B-RAF kinase inhibitor in preclinical species.
Choo et al. Xenobiotica. 2009 Sep;39(9):700-9. PMID: 19552528.
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.
Hoeflich et al. Cancer Res. 2009 Apr 1;69(7):3042-51. PMID: 19276360.
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.
Wong et al. J Pharmacol Exp Ther. 2009 Apr;329(1):360-7. PMID: 19147858.
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