B-RAF Inhibitors

Gene and Oncogene Targeting Team

Section: Cancer Research UK Cancer Therapeutics Unit

The Cancer Genome Project has identified mutations in B-RAF as its first major discovery. Mutations are present in 70% of melanomas, 10% of colorectal cancers and a smaller number of others cancers including early ovarian cancer. The mutations lead to constitutive activation of the kinase. The project aims to discover an inhibitor of B-RAF, preferably with selectivity for the mutant form for use in malignant melanoma and potentially other tumour types. High throughput screening of external and in-house libraries has been completed and has led to a number of hits. Taking into account the hits and the data obtained from modelling two series of potential inhibitors of BRAF were designed. Over 150 new potential inhibitors for B-RAF belonging to both series have been synthesised and assessed in vitro. A 1nM inhibitor of BRAF has been identified. In collaboration with Dr R Marais, Professor D Barford and colleagues, the crystal structure of B-RAF in complex with a small molecule inhibitor has been solved, and evidence validating B-RAF as a target in melanoma has been obtained.