Discovery of MAP855, an Efficacious and Selective MEK1/2 Inhibitor with an 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 MEK1/2 inhibitor with efficacy in wildtype (WT) and
mutant MEK12 models. Starting from a HTS hit, we obtained selective,
cellularly active compounds that showed equipotent inhibition of WT
MEK1/2 and a panel of MEK1/2 mutant cell lines. Using a structure-based
approach, the optimization addressed the liabilities by systematic
analysis of molecular matched pairs (MMPs) and ligand conformation.
Addition of only three heavy atoms to early tool compound 6 removed Cyp3A4 liabilities and increased the cellular potency by
100-fold, while reducing log P by 5 units. Profiling
of MAP855, compound 30, in pharmacokinetic–pharmacodynamic
and efficacy studies in BRAF-mutant models showed comparable efficacy
to clinical MEK1/2 inhibitors. Compound 30 is a novel
highly potent and selective MEK1/2 kinase inhibitor with equipotent
inhibition of WT and mutant MEK1/2, whose drug-like properties allow
further investigation in the mutant MEK setting upon BRAF/MEK therapy.