Discovery of MAP855, an Efficacious and Selective MEK1/2 Inhibitor with an ATP-Competitive Mode of Action

Abstract

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.

Application of Chiral Piperidine Scaffolds in Drug Design

“…16,17 In the process of identifying a new series of MEK1/2 inhibitors, the imidazoquinoline core was considered, and Poddutoori et al discovered 1-(piperidin-4-yl)-1Himidazo[4,5-c]quinoline ( 14) as a high-throughput screening hit, which had an acceptable MEK1/2 inhibition (EC 50 ¼ 400 nmol/L). 18 The structure-based design led to the discovery of analogue 15, whose MEK1/2 inhibition is eightfold higher than 14. Further optimization focused on the modification of the piperidine ring of 15, with a fluorine introduced at the 3position of the piperidine ring, to give chiral 16, which exhibited a further improved potency (EC 50 ¼ 5 nmol/L) and aqueous solubility (logP ¼ 1.6) as well as high oral bioavailability (F% ¼ 65) (►Fig.…”