BRAF Inhibitors

BRAF is a serine/threonine protein kinase, part of a pathway involved in cell division. Our colleagues Professors Michael Stratton, Chris Marshall and Richard Marais discovered that the BRAF gene is mutated in human cancers: ~ 50 % in melanomas and ~ 10 % in colorectal cancers. As a consequence of the mutation, the BRAF protein is constitutively activated in cells.

We have been working with Professor Richard Marais to discover inhibitors to inhibit proliferation in mutant BRAF driven cells in malignant melanoma, colorectal cancer and other tumour types.

High throughput screening of external and in-house compound libraries has been completed successfully. We have collaborated with Professors David Barford and Richard Marais to solve the crystal structure of BRAF complexed with small molecule inhibitors.

Five distinct series of potential inhibitors of BRAF have been designed and synthesised which bind both the inactive and the active conformation of the mutant BRAF enzyme (Figure 1 below). Over 600 novel compounds have now been synthesised and assessed in human cancer cells that are activated by mutant BRAF.

Many potent inhibitors of BRAF have been identified that, desirably, also inhibit CRAF, another member of the RAF family implicated in cancers. We have nominated 3 preclinical candidates and are currently preparing to progress the best to a clinical trial at the Royal Marsden Hospital.

Figure 1 Inhibitors binding to the inactive (A) and active (B) conformation of BRAF.