title: BAY 1143269, a novel MNK1 inhibitor, targets oncogenic protein expression and shows potent anti-tumor activity.
abstract: The initiation of mRNA translation has received increasing attention as an attractive target for cancer treatment in the recent years. The oncogenic eukaryotic translation initiation factor 4E (eIF4E) is the major substrate of MAP kinase-interacting kinase 1 (MNK1), and it is located at the junction of the cancer-associated PI3K and MAPK pathways. The fact that MNK1 is linked to cell transformation and tumorigenesis renders the kinase a promising target for cancer therapy. We identified a novel small molecule MNK1 inhibitor, BAY 1143269, by high-throughput screening and lead optimization. In kinase assays, BAY 1143269 showed potent and selective inhibition of MNK1. By targeting MNK1 activity, BAY 1143269 strongly regulated downstream factors involved in cell cycle regulation, apoptosis, immune response and epithelial-mesenchymal transition in vitro or in vivo. In addition, BAY 1143269 demonstrated strong efficacy in monotherapy in cell line and patient-derived non-small cell lung cancer xenograft models as well as delayed tumor regrowth in combination treatment with standard of care chemotherapeutics. In summary, the inhibition of MNK1 activity with a highly potent and selective inhibitor BAY 1143269 may provide an innovative approach for anti-cancer therapy.
authors.affiliation: Bayer AG, Drug Discovery, Pharmaceuticals, Müllerstr. 178, 13353 Berlin, Germany.
authors.forename: Susann
authors.initials: S
authors.lastname: Santag
authors.affiliation: Bayer AG, Drug Discovery, Pharmaceuticals, Müllerstr. 178, 13353 Berlin, Germany.
authors.forename: Franziska
authors.initials: F
authors.lastname: Siegel
authors.affiliation: Bayer AG, Drug Discovery, Pharmaceuticals, Müllerstr. 178, 13353 Berlin, Germany.
authors.forename: Antje M
authors.initials: AM
authors.lastname: Wengner
authors.affiliation: Bayer AG, Drug Discovery, Pharmaceuticals, Müllerstr. 178, 13353 Berlin, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Lange
authors.affiliation: Bayer AG, Drug Discovery, Pharmaceuticals, Müllerstr. 178, 13353 Berlin, Germany.
authors.forename: Ulf
authors.initials: U
authors.lastname: Bömer
authors.affiliation: Bayer AG, Drug Discovery, Pharmaceuticals, Müllerstr. 178, 13353 Berlin, Germany.
authors.forename: Knut
authors.initials: K
authors.lastname: Eis
authors.affiliation: Bayer AG, Drug Discovery, Pharmaceuticals, Müllerstr. 178, 13353 Berlin, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Pühler
authors.affiliation: Bayer AG, Drug Discovery, Pharmaceuticals, Müllerstr. 178, 13353 Berlin, Germany.
authors.forename: Philip
authors.initials: P
authors.lastname: Lienau
authors.affiliation: Bayer AG, Drug Discovery, Pharmaceuticals, Müllerstr. 178, 13353 Berlin, Germany.
authors.forename: Linda
authors.initials: L
authors.lastname: Bergemann
authors.affiliation: Bayer AG, Drug Discovery, Pharmaceuticals, Müllerstr. 178, 13353 Berlin, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Michels
authors.affiliation: Bayer AG, Drug Discovery, Pharmaceuticals, Müllerstr. 178, 13353 Berlin, Germany.
authors.forename: Franz
authors.initials: F
authors.lastname: von Nussbaum
authors.affiliation: Bayer AG, Drug Discovery, Pharmaceuticals, Müllerstr. 178, 13353 Berlin, Germany.
authors.forename: Dominik
authors.initials: D
authors.lastname: Mumberg
authors.affiliation: Bayer AG, Drug Discovery, Pharmaceuticals, Müllerstr. 178, 13353 Berlin, Germany. Electronic address: kirstin.petersen@bayer.com.
authors.forename: Kirstin
authors.initials: K
authors.lastname: Petersen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors*; D009857:Oncogenes / Q000235:genetics*; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011724:Pyridazines / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; C000622122:BAY 1143269; D007093:Imidazoles; D047908:Intracellular Signaling Peptides and Proteins; D047428:Protein Kinase Inhibitors; D011724:Pyridazines; C491395:MKNK1 protein, human; D017346:Protein Serine-Threonine Kinases
keywords: Anti-cancer therapy; MAP kinase-interacting kinase 1; Non-small cell lung cancer; Small molecule kinase inhibitor; eIF4E