Biological Activity
SB-590885 is a potent B-Raf inhibitor with Ki of 0.16 nM, and has 11-fold greater selectivity for B-Raf over c-Raf, without inhibition to other human kinases.
In Vitro
SB-590885 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). SB-590885 displays potent selectivity over 46 other kinases. Unlike the multi-kinase inhibitor BAY43-9006, SB-590885 stabilizes the oncogenic B-Raf kinase domain in an active configuration. In Colo205, HT29, A375P, SKMEL28, and MALME-3M cells expressing oncogenic B-RafV600E, SB-590885 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. SB-590885 decreases anchorage-independent growth of melanoma cell lines in a BRAF mutant-selective manner[1]. SB-590885 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 SB-590885 with IC50 of <1 μM. Increased levels of cyclin D1 resulting from genomic amplification mediate SB-590885 resistance in B-Raf V600E-mutated melanomas[3].
In Vivo
Administration of SB-590885 potently decreases tumorigenesis in murine xenografts established from mutant B-Raf-expressing A375P melanoma cells, and modestly inhibits tumor growth[1].
References & source
Published experimental findings depend on the model and assay conditions. They do not guarantee equivalent performance in every application. For laboratory research use only.
