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The Ras-Raf-MAPK signaling pathway plays a central role in diverse cellular processes including differentiation, proliferation and survival. This pathway is activated in a large percentage of cancers as a result of mutations in Ras or in B-Raf Ser/Thr kinase. The activating mutation V600E in B-Raf is present in approximately 60% of melanomas and occurs with lower, yet still significant, frequency in human colon and thyroid cancers. Hence, V600EB-Raf has received considerable interest as a small-molecule drug discovery target within the pharmaceutical industry. A high-throughput screen of Amgen's internal kinase preferred library against a recombinant V600EB-Raf kinase domain enzyme identified a class of biarylamide compounds as potent inhibitors of this kinase, and potential starting points for medicinal chemistry efforts. However, these compounds suffered from poor kinase selectivity, particularly against tyrosine kinases from the Src-, VEGFR and PDGFR-families. Crystal structures of representative examples of this scaffold in B-Raf and other tyrosine kinases identified a unique pocket in B-Raf that could be accessed to achieve selective inhibitors of this enzyme. Consequently a novel series of isoquinoline-based compounds was derived which demonstrated potent inhibition against V600EB-Raf enzyme and inhibition of MAPK pathway signaling in cell lines harboring V600EB-Raf. Further optimization within this inhibitor class yielded compounds with favorable in vivo properties as demonstrated by robust inhibition of ERK phosphorylation in V600EB-Raf driven pharmacodynamic models. Crystallographic work supporting the optimization of this series of selective B-Raf inhibitors will be presented. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2681A.