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

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

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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