Evaluation of: Niculescu-Duvaz D, Gaulon C, Dijkstra HP et al.: Pyridoimidazolones as novel potent inhibitors of v-Raf murine sarcoma viral oncogene homologue B1 (BRAF). J. Med. Chem. 52, 2255-2264 (2009). There are currently no therapies known to alter the clinical course of disseminated melanoma. Mutational profiling studies have shown that the majority of melanomas harbor activating mutations in the serine/threonine kinase BRAF at the V600E position. Preclinical work has validated mutated BRAF as a therapeutic target in melanoma, and a number of BRAF-selective small-molecule inhibitors are now undergoing clinical evaluation. The only BRAF inhibitor to be investigated extensively in clinical trials of melanoma at this time is sorafenib--a compound with very limited single-agent activity. As sorafenib has poor cellular activity against the BRAF V600E mutation, the conclusion that many researchers have arrived at is that sorafenib did not provide a test of the therapeutic value of BRAF inhibition. Thus, more highly selective BRAF inhibitors have been sought. The current paper describes the identification of a new class of BRAF inhibitors that contain pyridoimidazolone as the ATP hinge-binding domain and a rigid imidazolone group. Building upon this novel scaffold, the authors derived a series of compounds with low nanomolar potency against mutated BRAF in isolated kinase assays, and low micromolar potency in cellular assays. These new chemical leads represent a significant step forward in the search for new, potent BRAF-selective small-molecule inhibitors.