Moebitz, Henrik, Gruenenfelder, Bjoern, Kiffe, Michael, Ramos, Rita, Ramulu, Poddutoori, Kiran, Aithal, Mark, Bock, Sanjeev, BS, Shekar, Chelur, T S, Devaraja, Sreevalsam, Gopinath, Andrea, Gerken, Charamanna , KB, Maithreyi, Krishnaswami, John, Langowski, Sudarshan, Madapa, Kishore, Narayanan, Ravi Kumar , P, Chetan, Pandit, Sunil Kumar, Panigrahi, Mark, Perrone, Murali, Ramachandra, Anuradha, Ramanathan, Susanta, Samajdar, Hosahalli, Subramanya and Eleni, Venetsanakos (2022) Discovery of MAP855, an efficacious and selective MEK1/2 inhibitor with ATP-competitive mode of action. Journal of Medicinal Chemistry.

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 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.

Item Type:	Article
Date Deposited:	10 Mar 2022 00:45
Last Modified:	10 Mar 2022 00:45
URI:	https://oak.novartis.com/id/eprint/45499