title: Tricyclic covalent inhibitors selectively target Jak3 through an active site thiol.
abstract: The action of Janus kinases (JAKs) is required for multiple cytokine signaling pathways, and as such, JAK inhibitors hold promise for treatment of autoimmune disorders, including rheumatoid arthritis, inflammatory bowel disease, and psoriasis. However, due to high similarity in the active sites of the four members (Jak1, Jak2, Jak3, and Tyk2), developing selective inhibitors within this family is challenging. We have designed and characterized substituted, tricyclic Jak3 inhibitors that selectively avoid inhibition of the other JAKs. This is accomplished through a covalent interaction between an inhibitor containing a terminal electrophile and an active site cysteine (Cys-909). We found that these ATP competitive compounds are irreversible inhibitors of Jak3 enzyme activity in vitro. They possess high selectivity against other kinases and can potently (IC50 < 100 nm) inhibit Jak3 activity in cell-based assays. These results suggest irreversible inhibitors of this class may be useful selective agents, both as tools to probe Jak3 biology and potentially as therapies for autoimmune diseases.
authors.affiliation: From the AbbVie Bioresearch Center, Worcester, Massachusetts 01605. Electronic address: eric.goedken@abbvie.com.
authors.forename: Eric R
authors.initials: ER
authors.lastname: Goedken
authors.affiliation: From the AbbVie Bioresearch Center, Worcester, Massachusetts 01605.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Argiriadi
authors.affiliation: From the AbbVie Bioresearch Center, Worcester, Massachusetts 01605.
authors.forename: David L
authors.initials: DL
authors.lastname: Banach
authors.affiliation: From the AbbVie Bioresearch Center, Worcester, Massachusetts 01605.
authors.forename: Bryan A
authors.initials: BA
authors.lastname: Fiamengo
authors.affiliation: From the AbbVie Bioresearch Center, Worcester, Massachusetts 01605.
authors.forename: Sage E
authors.initials: SE
authors.lastname: Foley
authors.affiliation: From the AbbVie Bioresearch Center, Worcester, Massachusetts 01605.
authors.forename: Kristine E
authors.initials: KE
authors.lastname: Frank
authors.affiliation: From the AbbVie Bioresearch Center, Worcester, Massachusetts 01605.
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: George
authors.affiliation: From the AbbVie Bioresearch Center, Worcester, Massachusetts 01605.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Harris
authors.affiliation: From the AbbVie Bioresearch Center, Worcester, Massachusetts 01605.
authors.forename: Adrian D
authors.initials: AD
authors.lastname: Hobson
authors.affiliation: From the AbbVie Bioresearch Center, Worcester, Massachusetts 01605.
authors.forename: David C
authors.initials: DC
authors.lastname: Ihle
authors.affiliation: From the AbbVie Bioresearch Center, Worcester, Massachusetts 01605.
authors.forename: Douglas
authors.initials: D
authors.lastname: Marcotte
authors.affiliation: From the AbbVie Bioresearch Center, Worcester, Massachusetts 01605.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Merta
authors.affiliation: From the AbbVie Bioresearch Center, Worcester, Massachusetts 01605.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Michalak
authors.affiliation: From the AbbVie Bioresearch Center, Worcester, Massachusetts 01605.
authors.forename: Sara E
authors.initials: SE
authors.lastname: Murdock
authors.affiliation: From the AbbVie Bioresearch Center, Worcester, Massachusetts 01605.
authors.forename: Medha J
authors.initials: MJ
authors.lastname: Tomlinson
authors.affiliation: From the AbbVie Bioresearch Center, Worcester, Massachusetts 01605.
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Voss
mesh_terms: D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D001327:Autoimmune Diseases / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D020134:Catalytic Domain; D002460:Cell Line; D006801:Humans; D053616:Janus Kinase 3 / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology
chemical_list: D047428:Protein Kinase Inhibitors; D000255:Adenosine Triphosphate; C507933:JAK3 protein, human; D053616:Janus Kinase 3
keywords: Covalent Inhibitor; Cytokine; Drug Discovery; Enzyme Inhibitor; Enzyme Kinetics; Jak3; Janus Kinase (JAK); Tyrosine Kinase