GDC-0879

Alias: AR 00341677; GDC0879; AR00341677; AR-00341677; GDC-0879; GDC 0879
Cat No.:V1005 Purity: ≥98%
GDC-0879 (AR-00341677;GDC-0879; AR00341677) is a novel, potent, highly selective, and orally bioavailable B-Raf kinase inhibitor with potential antitumor activity.
GDC-0879 Chemical Structure CAS No.: 905281-76-7
Product category: Raf
This product is for research use only, not for human use. We do not sell to patients.
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Purity & Quality Control Documentation

Purity: ≥98%

Product Description

GDC-0879 (AR-00341677; GDC-0879; AR00341677) is a novel, potent, highly selective, and orally bioavailable B-Raf kinase inhibitor with potential antitumor activity. In A375 and Colo205 cells, it inhibits B-Raf kinase with an IC50 value of 0.13 nM. When compared to tumors derived from mutant KRAS-expressing mice, both cell line- and patient-derived BRAF(V600E) tumors showed stronger and longer-lasting pharmacodynamic inhibition (>90% for 8 hours). Cellular responses relevant to tumorigenesis, such as cell proliferation, invasion, survival, and angiogenesis, involve the Raf/mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase signaling pathway.

Biological Activity I Assay Protocols (From Reference)
Targets
B-Raf (IC50 = 0.13 nM)
ln Vitro
GDC-0879 also has an IC50 of 63 nM for inhibiting cellular pERK. GDC-0879 exhibits comparable potency in B-RafV600E mutant A375 melanoma and Colo205 colorectal carcinoma cell lines, with IC50 values for pMEK1 inhibition of 59 nM and 29 nM, respectively. With an IC50 of 0.75 μM , GDC-0879 potently inhibits B-RafV600E in Malme3M cells. Many tumor cells, including A375, 624, SK-MEL-28, Malme3M, C32, 928, 888, G-361, Colo205, Colo206, SW1417, CL34, and Colo201, exhibit EC50 values for GDC-0879 that are less than 0.5 μM.[1]
ln Vivo
Compared to mutant KRAS-expressing tumors, GDC-0879-treated mice with BRAFV600E tumors from both cell lines and patients show a stronger and longer-lasting pharmacodynamic inhibition (>90% for 8 hours). A decreased time to progression is seen for some KRAS-mutant tumors after GDC-0879 administration, despite the fact that activated RAF signaling is involved in RAS-induced tumorigenesis. Mek inhibition also inhibits proliferation and tumor growth in cell lines expressing wild-type BRAF (81% KRAS mutant, 38% KRAS wild type), in contrast to GDC-0879, whose efficacy is solely dependent on B-RafV600E status. Pharmacological and genetic modifications of the PI3K pathway activity may significantly alter the B-RafV600E melanoma cells' response to GDC-0879.[2]
Enzyme Assay
GDC-0879 is a potent and selective B-Raf inhibitor with an IC50 of 0.13 nM.
Cell Assay
GDC-0879 in vitro IC50 estimates for pMEK inhibition are determined using A375 and Colo205 cells. Briefly, GDC-0879 is incubated with A375 or Colo205 cells for 25 min at a range of concentrations (from 0.5 nM to 6.75 μM). Cells are lysed, and the lysates are centrifuged at 16,100 g for 30 min to determine the level of total protein. In a 96-well format, the levels of pMEK1 and total MEK1 protein are determined using enzyme-linked immunosorbent assay kits. At 20 μg of protein per well, samples are examined in duplicate. When converting optical densities obtained at 450 nm to units per milliliter (for pMEK1) or nanograms per milliliter (for total MEK1), a standard curve created using recombinant pMEK1 or MEK1 is used as a reference. Once converted to units per nanogram, the pMEK1/total MEK1 ratios are calculated. GraphPad Prism version 4.02 is used to estimate the IC50 values for pMEK1 inhibition through nonlinear regression.
Animal Protocol
Mice: GDC-0879 is given orally in doses of 15, 25, 50, 100, and 200 mg/kg to female athymic nu/nu mice (weighing 25–28 g). Through cardiac puncture (terminal collection), blood samples (~1 mL) are taken at intervals of 0.5, 1, 2, 4, 8, and 24 hours following the dose and placed into tubes containing K2EDTA anticoagulant. The blood is combined with K2EDTA as soon as it is drawn, then chilled. Within 30 minutes, plasma is extracted from blood samples that have been centrifuged at a speed of 1000 to 1500g for five minutes at 4°C. When not in use, the plasma samples are kept at -80°C.
References

[1]. Potent and selective pyrazole-based inhibitors of B-Raf kinase. Bioorg Med Chem Lett. 2008 Aug 15;18(16):4692-5.

[2]. 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.

These protocols are for reference only. InvivoChem does not independently validate these methods.
Physicochemical Properties
Molecular Formula
C19H18N4O2
Molecular Weight
334.37
Exact Mass
334.14
Elemental Analysis
C, 68.25; H, 5.43; N, 16.76; O, 9.57
CAS #
905281-76-7
Appearance
Solid powder
SMILES
C1C/C(=N\O)/C2=C1C=C(C=C2)C3=CN(N=C3C4=CC=NC=C4)CCO
InChi Key
DEZZLWQELQORIU-RELWKKBWSA-N
InChi Code
InChI=1S/C19H18N4O2/c24-10-9-23-12-17(19(21-23)13-5-7-20-8-6-13)15-1-3-16-14(11-15)2-4-18(16)22-25/h1,3,5-8,11-12,24-25H,2,4,9-10H2/b22-18+
Chemical Name
2-[4-[(1E)-1-hydroxyimino-2,3-dihydroinden-5-yl]-3-pyridin-4-ylpyrazol-1-yl]ethanol
Synonyms
AR 00341677; GDC0879; AR00341677; AR-00341677; GDC-0879; GDC 0879
HS Tariff Code
2934.99.9001
Storage

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Shipping Condition
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
Solubility Data
Solubility (In Vitro)
DMSO: ~66 mg/mL warming (~197.4 mM)
Water: <1 mg/mL
Ethanol: ~5 mg/mL (~15.0 mM)
Solubility (In Vivo)
0.5% methylcellulose+0.2% Tween 80: 8 mg/mL
 (Please use freshly prepared in vivo formulations for optimal results.)
Preparing Stock Solutions 1 mg 5 mg 10 mg
1 mM 2.9907 mL 14.9535 mL 29.9070 mL
5 mM 0.5981 mL 2.9907 mL 5.9814 mL
10 mM 0.2991 mL 1.4953 mL 2.9907 mL

*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.

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Note: Chemical formula is case sensitive: C12H18N3O4  c12h18n3o4
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Working concentration mg/mL;

Method for preparing DMSO stock solution mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.

Method for preparing in vivo formulation:Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O,mix and clarify.

(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
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Biological Data
  • GDC-0879

    GDC-0879 is a potent and selective RAF kinase inhibitor. Cancer Res. 2009 Apr 1;69(7):3042-51.

  • GDC-0879

    BRAFV600E mutation predicts for enhanced sensitivity of melanoma, colon, and lung cancer cell lines to RAF inhibitors in vitro.

  • GDC-0879

    Wild-type BRAF melanoma tumors have an attenuated pharmacodynamic response to GDC-0879 treatment relative to BRAFV600E tumor xenografts.

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