SB-590885

SB-590885 is a potent inhibitor of B-Raf (K_d = 0.3 nM).¹ It less effectively inhibits c-Raf (K_i = 1.72 nM) and has little effect at 46 other kinases.^1,2 SB-590885 blocks activation of ERK1/2 and anchorage-independent cell proliferation of melanoma cells with either wild type or V600E B-Raf at nanomolar concentrations.^2,3 Melanoma cells expressing the B-Raf^V600E mutation can drive invasion through alternative pathways in the presence of SB-590885, suggesting that combination therapy is needed to completely block cell invasion.³ SB-590885 has also been used to study the role of B-Raf in cerebral ischemia.⁴

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1. Takle, A.K., Bamford, M.J.B., Davies, S., et al. The identification of potent and selective imidazole-based inhibitors of B-Raf kinase. Bioorg. Med. Chem. Lett. 18(15), 4373-4376 (2008).

2. King, A.J., Patrick, D.R., Batorsky, R.S., et al. Demonstration of a genetic therapeutic index for tumors expressing oncogenic BRAF by the kinase inhibitor SB-590885. Cancer Res. 66(23), 11100-11105 (2006).

3. Klein, R.M., and Higgins, P.J. A switch in RND3-RHOA signaling is critical for melanoma cell invasion following mutant-BRAF inhibition. Mol. Cancer 10, 2-8 (2011).

4. Ahnstedt, H., Säveland, H., Nilsson, O., et al. Human cerebrovascular contractile receptors are upregulated via a B-Raf/MEK/ERK-sensitive signaling pathway. BMC Neurosci. 12, 1-9 (2011).