title: Selective JAK3 Inhibitors with a Covalent Reversible Binding Mode Targeting a New Induced Fit Binding Pocket.
abstract: Janus kinases (JAKs) are a family of cytoplasmatic tyrosine kinases that are attractive targets for the development of anti-inflammatory drugs given their roles in cytokine signaling. One question regarding JAKs and their inhibitors that remains under intensive debate is whether JAK inhibitors should be isoform selective. Since JAK3 functions are restricted to immune cells, an isoform-selective inhibitor for JAK3 could be especially valuable to achieve clinically more useful and precise effects. However, the high degree of structural conservation makes isoform-selective targeting a challenging task. Here, we present picomolar inhibitors with unprecedented kinome-wide selectivity for JAK3. Selectivity was achieved by concurrent covalent reversible targeting of a JAK3-specific cysteine residue and a ligand-induced binding pocket. We confirmed that in vitro activity and selectivity translate well into the cellular environment and suggest that our inhibitors are powerful tools to elucidate JAK3-specific functions.
authors.affiliation: Department of Pharmaceutical/Medicinal Chemistry, Eberhard-Karls-University Tuebingen, Auf der Morgenstelle 8, 72076 Tuebingen, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Forster
authors.affiliation: Nuffield Department of Clinical Medicine, Structural Genomics Consortium and Target Discovery Institute, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK.
authors.forename: Apirat
authors.initials: A
authors.lastname: Chaikuad
authors.affiliation: Department of Pharmaceutical/Medicinal Chemistry, Eberhard-Karls-University Tuebingen, Auf der Morgenstelle 8, 72076 Tuebingen, Germany.
authors.forename: Silke M
authors.initials: SM
authors.lastname: Bauer
authors.affiliation: Department of Dermatology, University Medical Center, Eberhard-Karls-University Tuebingen, Liebermeisterstraße 25, 72076 Tuebingen, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Holstein
authors.affiliation: Promega Corporation, 2800 Woods Hollow Road, Madison, WI 53711, USA.
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Robers
authors.affiliation: Promega Corporation, 2800 Woods Hollow Road, Madison, WI 53711, USA.
authors.forename: Cesear R
authors.initials: CR
authors.lastname: Corona
authors.affiliation: Department of Pharmaceutical/Medicinal Chemistry, Eberhard-Karls-University Tuebingen, Auf der Morgenstelle 8, 72076 Tuebingen, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Gehringer
authors.affiliation: Department of Pharmaceutical/Medicinal Chemistry, Eberhard-Karls-University Tuebingen, Auf der Morgenstelle 8, 72076 Tuebingen, Germany.
authors.forename: Ellen
authors.initials: E
authors.lastname: Pfaffenrot
authors.affiliation: Department of Dermatology, University Medical Center, Eberhard-Karls-University Tuebingen, Liebermeisterstraße 25, 72076 Tuebingen, Germany.
authors.forename: Kamran
authors.initials: K
authors.lastname: Ghoreschi
authors.affiliation: Nuffield Department of Clinical Medicine, Structural Genomics Consortium and Target Discovery Institute, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK. Electronic address: knapp@pharmchem.uni-frankfurt.de.
authors.forename: Stefan
authors.initials: S
authors.lastname: Knapp
authors.affiliation: Department of Pharmaceutical/Medicinal Chemistry, Eberhard-Karls-University Tuebingen, Auf der Morgenstelle 8, 72076 Tuebingen, Germany. Electronic address: stefan.laufer@uni-tuebingen.de.
authors.forename: Stefan A
authors.initials: SA
authors.lastname: Laufer
mesh_terms: D001665:Binding Sites / Q000187:drug effects; D055808:Drug Discovery; D006801:Humans; D053616:Janus Kinase 3 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D062105:Molecular Docking Simulation; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism
chemical_list: D047428:Protein Kinase Inhibitors; D053616:Janus Kinase 3
keywords: JAK3; Janus kinases; chemical probe; covalent reversible inhibitor; kinome selectivity