title: Identification of 8-Hydroxyquinoline Derivatives Active Against Somatic V658F Mutant JAK1-Dependent Cells.
abstract: Janus kinases (JAKs) and their gain-of-function mutants have been implicated in a range of oncological, inflammatory, and autoimmune conditions, which has sparked great research interest in the discovery and development of small-molecule JAK inhibitors. Two molecules are currently marketed as JAK inhibitors, but due to the displayed side effects (owing to their suboptimal selectivities among the various JAK subtypes) new JAK inhibitors are still sought after. We present the results of an extensive virtual screening campaign based on a multi-step screening protocol involving ligand docking. The screening yielded five new, experimentally validated inhibitors of JAK1 with 8-hydroxyquinoline as a novel hinge-binding scaffold. The compounds did not only display favorable potencies in a JAK1V658F-driven cell-based assay but were also shown to be non-cytotoxic on rat liver cells.
authors.affiliation: MTA-TTK-NAP B - Drug Discovery Research Group - Neurodegenerative Diseases, Research Center for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary.
authors.forename: Róbert
authors.initials: R
authors.lastname: Kiss
authors.affiliation: Medicinal Chemistry Research Group, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary.
authors.forename: Dávid
authors.initials: D
authors.lastname: Bajusz
authors.affiliation: Department of Physiology and Functional Genomics, University of Florida College of Medicine, Gainesville, FL, USA.
authors.forename: Rebekah
authors.initials: R
authors.lastname: Baskin
authors.affiliation: Metabolic Drug Interactions Research Group, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary.
authors.forename: Katalin
authors.initials: K
authors.lastname: Tóth
authors.affiliation: Metabolic Drug Interactions Research Group, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary.
authors.forename: Katalin
authors.initials: K
authors.lastname: Monostory
authors.affiliation: Department of Physiology and Functional Genomics, University of Florida College of Medicine, Gainesville, FL, USA.
authors.forename: Peter P
authors.initials: PP
authors.lastname: Sayeski
authors.affiliation: Medicinal Chemistry Research Group, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary.
authors.forename: György M
authors.initials: GM
authors.lastname: Keserű
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D053613:Janus Kinase 1 / Q000037:antagonists & inhibitors*; D051379:Mice; D062105:Molecular Docking Simulation; D009154:Mutation; D015125:Oxyquinoline / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D047428:Protein Kinase Inhibitors; D015125:Oxyquinoline; D053613:Janus Kinase 1
keywords: Docking; JAK1 inhibitor; Janus kinase; V658F/JAK1 cells; Virtual screening