Substance
ID:73743
Names and Identifiers
Synonyms
SB590885SB 590885
IUPAC Traditional name
[2-(4-{4-[(1E)-1-(hydroxyimino)-2,3-dihydroinden-5-yl]-5-(pyridin-4-yl)-3H-imidazol-2-yl}phenoxy)ethyl]dimethylamine
IUPAC name
[2-(4-{5-[(1E)-1-(hydroxyimino)-2,3-dihydro-1H-inden-5-yl]-4-(pyridin-4-yl)-1H-imidazol-2-yl}phenoxy)ethyl]dimethylamine
Registration numbers
CAS Number
Properties
Pharmacology Properties
Target
B-Raf
Safety Information
Storage Condition
-20°C
Product Information
Salt Data
Free Base
Molecule Details
Research Area
Description
Cancer
Biological Activity
Description
SB590885 is a potent B-Raf inhibitor with Ki of 0.16 nM.
Targets
B-Raf
IC50
0.16 nM (Ki) [1]
In Vitro
SB590885 displays significant selectivity for B-Raf over c-Raf with Ki of 0.16 nM over 1.72 nM. SB-590885 is a more potent inhibitor than the previously described Raf/VEGFR kinase inhibitor BAY 439006 (Ki = 38 nM for mutant B-Raf, 6 nM for c-Raf). SB590885 displays potent selectivity over 46 other kinases. Unlike the multi-kinase inhibitor BAY43-9006, SB590885 stabilizes the oncogenic B-Raf kinase domain in an active configuration. In Colo205, HT29, A375P, SKMEL28, and MALME-3M cells expressing oncogenic B-RafV600E, SB590885 treatment potently inhibits ERK phosphorylation with EC50 of 28 nM, 58 nM, 290 nM, 58 nM, and 190 nM, respectively, and consistently, inhibits the proliferation with EC50 of 0.1 μM, 0.87 μM, 0.37 μM, 0.12 μM, and 0.15 μM, respectively. SB590885 decreases anchorage-independent growth of melanoma cell lines in a BRAF mutant-selective manner. [1] SB590885 displays high affinity for B-Raf with Kd of 0.3 nM. [2] Most of the melanoma cell lines that harbor the BRAF V600E mutation and lack CDK4 mutations (451Lu, WM35, and WM983) are highly sensitive to SB590885 with IC50 of <1 μm.="" increased="" levels="" of="" cyclin="" d1="" resulting="" from="" genomic="" amplification="" mediate="" sb590885="" resistance="" in="" b-raf="" v600e-mutated="" melanomas.="">[3]
In Vivo
Administration of SB590885 potently decreases tumorigenesis in murine xenografts established from mutant B-Raf-expressing A375P melanoma cells, and modestly inhibits tumor growth. [1]
Clinical Trials
Features
SB590885 displays significant selectivity for B-Raf over c-Raf.
Protocol
Kinase Assay []
Cell Assay [1]
Cell Lines
Colo205, HT29, A375P, SKMEL28, and MALME-3M
Concentrations
Dissolved in DMSO, final concentrations ~10 μM
Incubation Time
72 hours
Methods
Cells are treated with increasing concentrations of SB590885 and incubated for 72 hours. Viable cells are quantified using CellTiter-Glo reagent and luminescence detection on a Victor 2V plate reader. Cells are prepared for cell cycle analysis on a Becton Dickinson FACScan. Data is acquired and analyzed using CellQuest v3.3 software.
Animal Study [1]
Animal Models
Female nude mice injected s.c. with of A375P cells
Formulation
Dissolved in vehicle [2% N,N-dimethylacetamide, 2% Cremophor EL, and 96% acidified water (pH f4–5)]
Doses
50 mg/kg/day
Administration
Injection i.p.
Molecular Spectra
No Data Available
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References
• Smalley KS, et al. Mol Cancer Ther, 2008, 7(9), 2876-2883.
• Takle AK, et al. Bioorg Med Chem Lett, 2006, 16(2), 378-381.
• King AJ, et al. Cancer Res, 2006, 66(23), 11100-11105.