BRAF is a serine/threonine specific protein kinase component of the RAS-ERK signalling pathway. BRAF is mutated in ~50% malignant melanomas, where it is avalidated oncogene driver and therapeutic target. Inhibitors to target mutant BRAF have been developed and the most advanced of these, PLX4032, is in Phase III clinical trials with responses in >80% of patients with BRAF mutations. However, the responses are limited with all patients eventually developing resistance. Furthermore, 30% of patients on this drug develop keratoacanthomas/squamous cell carcinomas (SCC). With Trust funding, we have designed, synthesised and selected 3 preclinical BRAF inhibitors with properties and selectivity profiles different from PLX4032. We believe any of our 3 inhibitors will be effective in mutant BRAF driven melanomas and, unlike PLX4032, our inhibitors will also be effective in mutant NRAS driven cancers and elicit lower incidences of SCC. We propose to conduct a Phase I clinical trial with one of our inhibitors to test its performance, The project involves the preclinical development of our BRAF inhibitors, which will include: (1) CRO dog pharmacokinetics on three of our inhibitors, (2) CRO non-GLP dog and rat toxicity studies on two inhibitorsselected from (1) (3) CRO GLP toxicity studies of one inhibitor selected from (2) (4) A clinical trial on the inhibitor from (3) in melanoma patients. 8 Our aim is to develop one of our inhibitors, with the objective of showing improved progression-free-survival and/or reduced SCC rates relative to PLX4032 and also to investigate the selected inhibitor in treatment naive mutant BRAF patients, PLX4032 refractory patients and in NRAS mutant patients.