Discovery of MAP855, an efficacious and selective MEK1/2 inhibitor with ATP-competitive mode of action

Mutations in MEK1/2 have been described as a resistance mechanism to BRAF/MEK inhibitor treatment. We report the discovery of a novel ATP-competitive MEK inhibitor with efficacy in wildtype (WT) and mutant MEK models. Starting from a HTS hit, we obtained selective, cellularly active compounds that showed equipotent inhibition of WT MEK and a panel of MEK mutant cell lines. Using a structure-based approach, the optimisation addressed the liabilities by systematic analysis of molecular matched pairs (MMP) and ligand conformation. Addition of only 3 heavy atoms to early tool com-pound 6 removed Cyp3A4 liabilities and increased cellular potency by 100-fold, while reducing logP by 5 units. Profiling of MAP855, compound 30 in PK-PD and efficacy studies in BRAF-mutant models showed comparable efficacy to clinical MEK inhibitors. Compound 30 is a novel highly potent and selective MEK1 kinase inhibitor with equipotent inhibition of WT and mutant MEK whose drug like properties allow further investigation in the mutant MEK setting upon BRAF/MEK therapy