Q1 · MEDICINE
Article
Author: Bock, Mark ; Langowski, John ; Perrone, Mark ; Ramanathan, Anuradha ; Chelur, Shekar ; Pandit, Chetan ; Möbitz, Henrik ; Aithal, Kiran ; Panigrahi, Sunil Kumar ; Gerken, Andrea ; Ramachandra, Murali ; Sager, Emine ; Barahagar, Sanjeev Surendranath ; Subramanya, Hosahalli S. ; Gopinath, Sreevalsam ; Gruenenfelder, Bjoern ; Venetsanakos, Eleni ; Kiffe, Michael ; Thimmasandra, Devaraja Seethappa ; Narayanan, Kishore ; Aardalen, Kimberly ; Samajdar, Susanta ; Potakamuri, Ravi Kumar ; Krishnaswami, Maithreyi ; Belliappa, Charamanna ; Ramos, Rita ; Poddutoori, Ramulu ; Madapa, Sudharshan
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.