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

Autor:	Ramulu Poddutoori, Kimberly Aardalen, Kiran Aithal, Sanjeev Surendranath Barahagar, Charamanna Belliappa, Mark Bock, Shekar Chelur, Andrea Gerken, Sreevalsam Gopinath, Bjoern Gruenenfelder, Michael Kiffe, Maithreyi Krishnaswami, John Langowski, Sudharshan Madapa, Kishore Narayanan, Chetan Pandit, Sunil Kumar Panigrahi, Mark Perrone, Ravi Kumar Potakamuri, Murali Ramachandra, Anuradha Ramanathan, Rita Ramos, Emine Sager, Susanta Samajdar, Hosahalli S. Subramanya, Devaraja Seethappa Thimmasandra, Eleni Venetsanakos, Henrik Möbitz
Rok vydání:	2022
Předmět:	Mitogen-Activated Protein Kinase Kinases Proto-Oncogene Proteins B-raf Adenosine Triphosphate Cell Line Tumor Mutation Drug Discovery MAP Kinase Kinase 1 Molecular Medicine Protein Kinase Inhibitors
Zdroj:	Journal of Medicinal Chemistry. 65:4350-4366
ISSN:	1520-4804 0022-2623
DOI:	10.1021/acs.jmedchem.1c02192
Popis:	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
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::7df3980bf0fc9797eb2d0401e08b1d0f https://doi.org/10.1021/acs.jmedchem.1c02192 Zobrazit plný text záznamu