title: Development of Selective Covalent Janus Kinase 3 Inhibitors.
abstract: The Janus kinases (JAKs) and their downstream effectors, signal transducer and activator of transcription proteins (STATs), form a critical immune cell signaling circuit, which is of fundamental importance in innate immunity, inflammation, and hematopoiesis, and dysregulation is frequently observed in immune disease and cancer. The high degree of structural conservation of the JAK ATP binding pockets has posed a considerable challenge to medicinal chemists seeking to develop highly selective inhibitors as pharmacological probes and as clinical drugs. Here we report the discovery and optimization of 2,4-substituted pyrimidines as covalent JAK3 inhibitors that exploit a unique cysteine (Cys909) residue in JAK3. Investigation of structure-activity relationship (SAR) utilizing biochemical and transformed Ba/F3 cellular assays resulted in identification of potent and selective inhibitors such as compounds 9 and 45. A 2.9 Å cocrystal structure of JAK3 in complex with 9 confirms the covalent interaction. Compound 9 exhibited decent pharmacokinetic properties and is suitable for use in vivo. These inhibitors provide a set of useful tools to pharmacologically interrogate JAK3-dependent biology.
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School , Boston, Massachusetts 02115, United States.
authors.forename: Li
authors.initials: L
authors.lastname: Tan
authors.forename: Koshi
authors.initials: K
authors.lastname: Akahane
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School , Boston, Massachusetts 02115, United States.
authors.forename: Randall
authors.initials: R
authors.lastname: McNally
authors.affiliation: Division of Cell Signaling and Immunology, College of Life Sciences, University of Dundee , Dundee DD1 5EH. U.K.
authors.forename: Kathleen M S E
authors.initials: KM
authors.lastname: Reyskens
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School , Boston, Massachusetts 02115, United States.
authors.forename: Scott B
authors.initials: SB
authors.lastname: Ficarro
authors.forename: Suhu
authors.initials: S
authors.lastname: Liu
authors.forename: Grit S
authors.initials: GS
authors.lastname: Herter-Sprie
authors.forename: Shohei
authors.initials: S
authors.lastname: Koyama
authors.affiliation: Division of Cell Signaling and Immunology, College of Life Sciences, University of Dundee , Dundee DD1 5EH. U.K.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Pattison
authors.forename: Katherine
authors.initials: K
authors.lastname: Labella
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School , Boston, Massachusetts 02115, United States.
authors.forename: Liv
authors.initials: L
authors.lastname: Johannessen
authors.forename: Esra A
authors.initials: EA
authors.lastname: Akbay
authors.forename: Kwok-Kin
authors.initials: KK
authors.lastname: Wong
authors.forename: David A
authors.initials: DA
authors.lastname: Frank
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School , Boston, Massachusetts 02115, United States.
authors.forename: Jarrod A
authors.initials: JA
authors.lastname: Marto
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Look
authors.affiliation: Division of Cell Signaling and Immunology, College of Life Sciences, University of Dundee , Dundee DD1 5EH. U.K.
authors.forename: J Simon C
authors.initials: JS
authors.lastname: Arthur
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School , Boston, Massachusetts 02115, United States.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Eck
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School , Boston, Massachusetts 02115, United States.
authors.forename: Nathanael S
authors.initials: NS
authors.lastname: Gray
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D001682:Biological Availability; D045744:Cell Line, Tumor; D002470:Cell Survival; D006801:Humans; D053616:Janus Kinase 3 / Q000037:antagonists & inhibitors*; D008297:Male; D051379:Mice; D008958:Models, Molecular; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D053616:Janus Kinase 3