SB-590885 is a selective small-molecule inhibitor of the B-Raf kinase and Ki app values are 0.16 and 1.72 nM for B-Raf and c-Raf respectively. SB590885 has been used to overcome the dependence of MAPK signaling and tumor cell growth on BRaf kinase activity. In melanoma and colorectal cancer cell lines with B-Raf V600E mutation, an effective inhibition of cell proliferation was achieved at concentrations that blocked ERK phosphorylation. The inhibition of MAP kinase is one of the vital ways to get rid of un-wanted tumor growth. SB590885 also act as an angiogenesis inhibitor and also helps in the research studies of different important kinase pathways.
|Cell lines||Colo205, HT-1080, HT-29, A395p and SK-MEL28 cells line|
|Preparation method||Cellular assays.
For proliferation assays, cells were treated with compounds in 0.1% DMSO and incubated for 72 hours at 37°C, 5% CO2. Viable cells were quantified using CellTiter-Glo reagent (Promega, Madison, WI) and luminescence detection on a Victor 2V plate reader (Perkin-Elmer, Turku, Finland). Cells were prepared for cell cycle analysis on a Becton Dickinson FACScan, according to the manufacturer's instructions. Data was acquired and analyzed using CellQuest v3.3 software. Anchorage-independent growth assays were done as described elsewhere ( 6), with inhibitors or DMSO vehicle included in the agar layer. Cultures were re-fed with media and inhibitor or DMSO every 5 to 7 days for a total of 28 days. Colonies were visualized and photographed by conventional light microscopy and quantified by counting on a grid in triplicate.
|Concentrations||0.1, 1 and 10 μ M|
|Incubation time||72 h|
|Animal models||A375P xenograft model|
|Formulation||2% N,N-dimethylacetamide, 2% Cremophor EL, and 96% acidified water (pH ∼4-5)|
|Dosages||50 mg/kg daily for 21 days|
|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.
|Solubility||DMSO 5 mg/mL|
|Source||J Cell Mol Med (2015). Figure 2. SB590885|
|Cell Lines||TT cells|
|Incubation Time||72 hrs|
|Results||RAF265 was the most effective compound, showing an IC50 = 0.09 μM, while SB590885 showed an IC50 = 3.36 μM, and ZSTK474 an IC50 = 0.59 μM|
The identification of potent, selective and CNS penetrant furan-based inhibitors of B-Raf kinase.
Takle AK, et al. Bioorg Med Chem Lett. 2008 Aug 1;18(15):4373-6. PMID: 18621524.
Demonstration of a genetic therapeutic index for tumors expressing oncogenic BRAF by the kinase inhibitor SB-590885.
King AJ, et al. Cancer Res. 2006 Dec 1;66(23):11100-5. PMID: 17145850.
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