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

  • J Med Chem. 2022 Mar 10;65(5):4350-4366. doi: 10.1021/acs.jmedchem.1c02192.
Ramulu Poddutoori  1 ,  Kimberly Aardalen  2 ,  Kiran Aithal  1 ,  Sanjeev Surendranath Barahagar  1 ,  Charamanna Belliappa  1 ,  Mark Bock  3 ,  Shekar Chelur  1 ,  Andrea Gerken  3 ,  Sreevalsam Gopinath  1 ,  Bjoern Gruenenfelder  4 ,  Michael Kiffe  4 ,  Maithreyi Krishnaswami  1 ,  John Langowski  2 ,  Sudharshan Madapa  1 ,  Kishore Narayanan  1 ,  Chetan Pandit  1 ,  Sunil Kumar Panigrahi  1 ,  Mark Perrone  3 ,  Ravi Kumar Potakamuri  1 ,  Murali Ramachandra  1 ,  Anuradha Ramanathan  1 ,  Rita Ramos  5 ,  Emine Sager  4 ,  Susanta Samajdar  1 ,  Hosahalli S Subramanya  1 ,  Devaraja Seethappa Thimmasandra  1 ,  Eleni Venetsanakos  2 ,  Henrik Möbitz  4
Affiliations
  • 1. Aurigene Discovery Technologies Ltd, 39-40 KIADB Industrial Area, Electronic City Phase II, Bengaluru 560100, India.
  • 2. Novartis Institutes for BioMedical Research, 5300 Chiron Way, Emeryville, California 94608, United States.
  • 3. Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, United States.
  • 4. Novartis Institutes for BioMedical Research, Basel 4002, Switzerland.
  • 5. Global Drug Discovery, Novartis Pharma AG, Basel 4002, Switzerland.
PMID: 35195996 DOI: 10.1021/acs.jmedchem.1c02192
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.

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