SB590885

• Catalog No.: S2220
• CAS Number: 405554-55-4
• M. F.: C27H27N5O2
• M. W.: 453.53558
• Storage: -20°C

SYNONYMS

• 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
• 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
• Synonyms: SB 590885

DATABASE IDS

• CAS Number: 405554-55-4

PROPERTIES

• Target: B-Raf
• Salt Data: Free Base
• Storage Condition: -20°C

DETAILS

Description (English)

Research Area

• Description: Cancer

Biological Activity

• Description: SB590885 is a potent B-Raf inhibitor with K_i of 0.16 nM.
• Targets: B-Raf
• IC50: 0.16 nM (K_i) ^[1]
• In Vitro: SB590885 displays significant selectivity for B-Raf over c-Raf with K_i 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 (K_i = 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]
• Features: SB590885 displays significant selectivity for B-Raf over c-Raf.

Protocol

• Protocol: 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.
• Protocol: 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.

References

• References: [1] King AJ, et al. Cancer Res, 2006, 66(23), 11100-11105.
• References: [2] Takle AK, et al. Bioorg Med Chem Lett, 2006, 16(2), 378-381.
• References: [3] Smalley KS, et al. Mol Cancer Ther, 2008, 7(9), 2876-2883.

REFERENCES

• King AJ, et al. Cancer Res, 2006, 66(23), 11100-11105.
• Takle AK, et al. Bioorg Med Chem Lett, 2006, 16(2), 378-381.
• Smalley KS, et al. Mol Cancer Ther, 2008, 7(9), 2876-2883.