Type I, I½ and type II RAF inhibitors (RAFi) each bind to different conformations of RAF. (A) Type I RAFi bind to a closed, active conformation of RAF with DFG-in, αC-helix-in. Whilst this is effective for the inhibition of class I BRAF mutants, the closed conformation is conducive to dimerisation of wild-type RAF. Because class I RAFi are specific for BRAF this means the CRAF dimer partner is uninhibited by class I RAFi and thus is transactivated. (B) Type I½ RAFi bind to a DFG-in, αC-helix-out conformation. These inhibitors lower the binding affinity for the dimer partner because of the partial disruption of the dimerisation interface, as the binding of a second inhibitor would require breaking the dimer which is not energetically favoured at low concentrations of inhibitor. High concentrations of type I½ RAFi are able to inhibit both dimer partners and prevent pathway activation. (C) Type II RAFi bind to a DFG-out, αC-helix-in conformation. As type II inhibitors are pan-RAF rather than BRAF-selective they are able to inhibit pathway signalling despite promoting RAF dimerisation. (D) The structures of Vemurafenib, PLX7904, PLX8394 and LY3009120. Vemurafenib was used as a skeleton for the development of PLX7904, which was then optimised into PLX8394 to selectively target BRAF^V600E/K [92]. Whilst LY3009120 shares some structural similarities with vemurafenib, PLX7904 and PLX8394, LY3009120 does not contain a sulphonamide group and is a pan-RAF inhibitor targeting both BRAF and CRAF.