title: Discovery of selective RIO2 kinase small molecule ligand.
abstract: We report the discovery and initial optimization of diphenpyramide and several of its analogs as hRIO2 kinase ligands. One of these analogs is the most selective hRIO2 ligand reported to date. Diphenpyramide is a Cyclooxygenase 1 and 2 inhibitor that was used as an anti-inflammatory agent. The RIO2 kinase affinity of diphenpyramide was discovered by serendipity while profiling of 13 marketed drugs on a large 456 kinase assay panel. The inhibition values also suggested a relative selectivity of diphenpyramide for RIO2 against the other kinases in the panel. Subsequently three available and eight newly synthesized analogs were assayed, one of which showed a 10 fold increased hRIO2 binding affinity. Additionally, this compound shows significantly better selectivity over assayed kinases, when compared to currently known RIO2 inhibitors. As RIO2 is involved in the biosynthesis of the ribosome and cell cycle regulation, our selective ligand may be useful for the delineation of the biological role of this kinase. This article is part of a Special Issue entitled: Inhibitors of Protein Kinases.
authors.affiliation: Eli Lilly and Company, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46285, USA. Electronic address: varin_thibault@lilly.com.
authors.forename: Thibault
authors.initials: T
authors.lastname: Varin
authors.affiliation: Eli Lilly and Company, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46285, USA.
authors.forename: Alexander G
authors.initials: AG
authors.lastname: Godfrey
authors.affiliation: Eli Lilly and Company, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46285, USA.
authors.forename: Thierry
authors.initials: T
authors.lastname: Masquelin
authors.affiliation: Eli Lilly and Company, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46285, USA.
authors.forename: Christos A
authors.initials: CA
authors.lastname: Nicolaou
authors.affiliation: Eli Lilly and Company, Lilly Research Laboratories, Erl Wood Manor, Windlesham, Surrey GU206PH, UK.
authors.forename: David A
authors.initials: DA
authors.lastname: Evans
authors.affiliation: Eli Lilly and Company, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46285, USA.
authors.forename: Michal
authors.initials: M
authors.lastname: Vieth
mesh_terms: D000081:Acetamides / Q000737:chemistry; D018797:Cell Cycle Proteins / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008024:Ligands; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000737:chemistry*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D012270:Ribosomes / Q000187:drug effects / Q000378:metabolism*
chemical_list: D000081:Acetamides; D018797:Cell Cycle Proteins; D008024:Ligands; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; C542171:RIOK2 protein, human; C015136:difenpiramide
keywords: Cyclooxygenase inhibitor; DiscoverX ScanMax panel; Kinase inhibitor; Kinase selectivity profile; RIO2 kinase