product name SB590885
Description: SB590885 is a B-Raf inhibitor with Ki of 0.16 nM in a cell-free assay, 11-fold higher selectivity for B-Raf over c-Raf, it does not inhibit other kinases. It is found that SB590885 binds to B-Raf within the ATP-binding pocket and stabilizes the active conformation of B-Raf. SB590885 decreases the phosphorylation of ERK and shows anti-proliferation only in tumor cells expressing oncogenic B-Raf V600E.
References: Cancer Res. 2006 Dec 1;66(23):11100-5; Bioorg Med Chem Lett. 2006 Jan 15;16(2):378-81.
453.54
Formula
C27H27N5O2
CAS No.
405554-55-4
Storage
-20℃ for 3 years in powder form
-80℃ for 2 years in solvent
Solubility (In vitro)
DMSO: 5 mg/mL (11.0 mM)
Water: <1 mg/mL
Ethanol: <1 mg/mL
Solubility (In vivo)
2% Cremophor EL, 2% N,N-dimethylacetamide, pH 5.0: 30mg/mL
Synonyms
other peoduct :
| In Vitro |
In vitro activity: 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. SB590885 displays high affinity for B-Raf with Kd of 0.3 nM. 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. Kinase Assay: Cell Assay: 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. |
|---|---|
| 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. |
| Animal model | Female nude mice injected s.c. with of A375P cells |
| Formulation & Dosage | Dissolved in vehicle [2% N,N-dimethylacetamide, 2% Cremophor EL, and 96% acidified water (pH f4-5)]; 50 mg/kg; i.p. injection |
| References | Cancer Res. 2006 Dec 1;66(23):11100-5; Bioorg Med Chem Lett. 2006 Jan 15;16(2):378-81. |
