title: Discovery of a Selective and Potent Inhibitor of Mitogen-Activated Protein Kinase-Interacting Kinases 1 and 2 (MNK1/2) Utilizing Structure-Based Drug Design.
abstract: The discovery of a highly potent and selective small molecule inhibitor 9 for in vitro target validation of MNK1/2 kinases is described. The aminopyrazine benzimidazole series was derived from an HTS hit and optimized by utilization of a docking model, conformation analysis, and binding pocket comparison against antitargets.
authors.affiliation: Global Discovery Chemistry, Novartis Institutes for BioMedical Research , 4560 Horton Street, Emeryville, California 94608, United States.
authors.forename: Wooseok
authors.initials: W
authors.lastname: Han
authors.affiliation: Global Discovery Chemistry, Novartis Institutes for BioMedical Research , 4560 Horton Street, Emeryville, California 94608, United States.
authors.forename: Yu
authors.initials: Y
authors.lastname: Ding
authors.affiliation: Global Discovery Chemistry, Novartis Institutes for BioMedical Research , 4560 Horton Street, Emeryville, California 94608, United States.
authors.forename: Yongjin
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Global Discovery Chemistry, Novartis Institutes for BioMedical Research , 4560 Horton Street, Emeryville, California 94608, United States.
authors.forename: Keith
authors.initials: K
authors.lastname: Pfister
authors.affiliation: Global Discovery Chemistry, Novartis Institutes for BioMedical Research , 4560 Horton Street, Emeryville, California 94608, United States.
authors.forename: Shejin
authors.initials: S
authors.lastname: Zhu
authors.affiliation: Oncology, Novartis Institutes for BioMedical Research , 4560 Horton Street, Emeryville, California 94608, United States.
authors.forename: Bob
authors.initials: B
authors.lastname: Warne
authors.affiliation: Oncology, Novartis Institutes for BioMedical Research , 4560 Horton Street, Emeryville, California 94608, United States.
authors.forename: Mike
authors.initials: M
authors.lastname: Doyle
authors.affiliation: Oncology, Novartis Institutes for BioMedical Research , 4560 Horton Street, Emeryville, California 94608, United States.
authors.forename: Mina
authors.initials: M
authors.lastname: Aikawa
authors.affiliation: Oncology, Novartis Institutes for BioMedical Research , 4560 Horton Street, Emeryville, California 94608, United States.
authors.forename: Payman
authors.initials: P
authors.lastname: Amiri
authors.affiliation: Global Discovery Chemistry, Novartis Institutes for BioMedical Research , 4560 Horton Street, Emeryville, California 94608, United States.
authors.forename: Brent
authors.initials: B
authors.lastname: Appleton
authors.affiliation: Oncology, Novartis Institutes for BioMedical Research , 4560 Horton Street, Emeryville, California 94608, United States.
authors.forename: Darrin D
authors.initials: DD
authors.lastname: Stuart
authors.affiliation: Oncology, Novartis Institutes for BioMedical Research , 4560 Horton Street, Emeryville, California 94608, United States.
authors.forename: Abdallah
authors.initials: A
authors.lastname: Fanidi
authors.affiliation: Global Discovery Chemistry, Novartis Institutes for BioMedical Research , 4560 Horton Street, Emeryville, California 94608, United States.
authors.forename: Cynthia M
authors.initials: CM
authors.lastname: Shafer
mesh_terms: D001665:Binding Sites; D018938:Caco-2 Cells / Q000187:drug effects; D015195:Drug Design; D057166:High-Throughput Screening Assays / Q000379:methods; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D062105:Molecular Docking Simulation; D010539:Permeability; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D012995:Solubility; D013329:Structure-Activity Relationship
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D047428:Protein Kinase Inhibitors; C491395:MKNK1 protein, human; C486342:MKNK2 protein, human; D017346:Protein Serine-Threonine Kinases