B-RAF mutations have been identified in the majority of melanoma and a large fraction of colorectal and papillary thyroid carcinoma. Drug discovery efforts targeting mutated B-RAF have yielded several interesting molecules, and currently, three compounds are undergoing clinical evaluation. Inhibition of B-RAF in animal models leads to a slowing of tumor growth and, in some cases, tumor reduction. Described within is a novel series of diaryl imidazoles with potent, single-digit nanomolar, anti-B-RAF activity. One compound from this series has been detailed here and has been shown to block B-RAF(V600E)-dependent extracellular signal-regulated kinase 1/2 phosphorylation in SK-MEL-28 melanoma cells as well as soft agar colony formation and proliferation. Importantly, interleukin-8 (IL-8) was identified by quantitative real-time PCR and ELISA as a product of the elevated mitogen-activated protein kinase signaling in these cells. Plasma concentrations of IL-8 in mice bearing melanoma xenografts were significantly reduced following exposure to B-RAF inhibitors. Taken together, these data suggest that IL-8 could serve as a tractable clinical biomarker. [Mol Cancer Ther 2008;7(3):492-9].

Crawford S, Belajic D, Wei J, Riley JP, Dunford PJ, Bembenek S, Fourie A, Edwards JP, Karlsson L, Brunmark A, Wolin RL, Blevitt JM.

Department of Immunology, Johnson & Johnson Pharmaceutical Research & Development, LLC, 3210 Merryfield Row, La Jolla, CA 92121. jblevitt@prdus.jnj.com.