title: Identification of azabenzimidazoles as potent JAK1 selective inhibitors.
abstract: We have identified a class of azabenzimidazoles as potent and selective JAK1 inhibitors. Investigations into the SAR are presented along with the structural features required to achieve selectivity for JAK1 versus other JAK family members. An example from the series demonstrated highly selective inhibition of JAK1 versus JAK2 and JAK3, along with inhibition of pSTAT3 in vivo, enabling it to serve as a JAK1 selective tool compound to further probe the biology of JAK1 selective inhibitors.
authors.affiliation: AstraZeneca R&D Boston, Oncology IMED, 35 Gatehouse Drive, Waltham, MA 02451, United States. Electronic address: melissa.vasbinder@astrazeneca.com.
authors.forename: Melissa M
authors.initials: MM
authors.lastname: Vasbinder
authors.affiliation: AstraZeneca R&D Boston, Oncology IMED, 35 Gatehouse Drive, Waltham, MA 02451, United States.
authors.forename: Marat
authors.initials: M
authors.lastname: Alimzhanov
authors.affiliation: Proteros Biostructures GmbH, Martinsried, D-82152, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Augustin
authors.affiliation: AstraZeneca R&D Boston, Oncology IMED, 35 Gatehouse Drive, Waltham, MA 02451, United States.
authors.forename: Geraldine
authors.initials: G
authors.lastname: Bebernitz
authors.affiliation: AstraZeneca R&D Boston, Oncology IMED, 35 Gatehouse Drive, Waltham, MA 02451, United States.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Bell
authors.affiliation: AstraZeneca R&D Boston, Oncology IMED, 35 Gatehouse Drive, Waltham, MA 02451, United States.
authors.forename: Claudio
authors.initials: C
authors.lastname: Chuaqui
authors.affiliation: AstraZeneca R&D Boston, Oncology IMED, 35 Gatehouse Drive, Waltham, MA 02451, United States.
authors.forename: Tracy
authors.initials: T
authors.lastname: Deegan
authors.affiliation: AstraZeneca R&D Boston, Discovery Sciences, 35 Gatehouse Drive, Waltham, MA 02451, United States.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Ferguson
authors.affiliation: AstraZeneca R&D Boston, Oncology IMED, 35 Gatehouse Drive, Waltham, MA 02451, United States.
authors.forename: Kelly
authors.initials: K
authors.lastname: Goodwin
authors.affiliation: AstraZeneca R&D Boston, Oncology IMED, 35 Gatehouse Drive, Waltham, MA 02451, United States.
authors.forename: Dennis
authors.initials: D
authors.lastname: Huszar
authors.affiliation: AstraZeneca R&D Boston, Oncology IMED, 35 Gatehouse Drive, Waltham, MA 02451, United States.
authors.forename: Aarti
authors.initials: A
authors.lastname: Kawatkar
authors.affiliation: AstraZeneca R&D Boston, Oncology IMED, 35 Gatehouse Drive, Waltham, MA 02451, United States.
authors.forename: Sameer
authors.initials: S
authors.lastname: Kawatkar
authors.affiliation: AstraZeneca R&D, Discovery Sciences, Darwin Building, 310 Cambridge Science Park, Milton Road, Cambridge CB4 0WG, UK.
authors.forename: Jon
authors.initials: J
authors.lastname: Read
authors.affiliation: AstraZeneca R&D Boston, Oncology IMED, 35 Gatehouse Drive, Waltham, MA 02451, United States.
authors.forename: Jie
authors.initials: J
authors.lastname: Shi
authors.affiliation: Proteros Biostructures GmbH, Martinsried, D-82152, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Steinbacher
authors.affiliation: Proteros Biostructures GmbH, Martinsried, D-82152, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Steuber
authors.affiliation: AstraZeneca R&D Boston, Oncology IMED, 35 Gatehouse Drive, Waltham, MA 02451, United States.
authors.forename: Qibin
authors.initials: Q
authors.lastname: Su
authors.affiliation: AstraZeneca R&D Boston, Oncology IMED, 35 Gatehouse Drive, Waltham, MA 02451, United States.
authors.forename: Dorin
authors.initials: D
authors.lastname: Toader
authors.affiliation: AstraZeneca R&D Boston, Oncology IMED, 35 Gatehouse Drive, Waltham, MA 02451, United States.
authors.forename: Haixia
authors.initials: H
authors.lastname: Wang
authors.affiliation: AstraZeneca R&D Boston, Oncology IMED, 35 Gatehouse Drive, Waltham, MA 02451, United States.
authors.forename: Richard
authors.initials: R
authors.lastname: Woessner
authors.affiliation: AstraZeneca R&D Boston, Discovery Sciences, 35 Gatehouse Drive, Waltham, MA 02451, United States.
authors.forename: Allan
authors.initials: A
authors.lastname: Wu
authors.affiliation: AstraZeneca R&D Boston, Oncology IMED, 35 Gatehouse Drive, Waltham, MA 02451, United States.
authors.forename: Minwei
authors.initials: M
authors.lastname: Ye
authors.affiliation: AstraZeneca R&D Boston, Oncology IMED, 35 Gatehouse Drive, Waltham, MA 02451, United States.
authors.forename: Michael
authors.initials: M
authors.lastname: Zinda
mesh_terms: D000818:Animals; D002453:Cell Cycle / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D053613:Janus Kinase 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D050796:STAT3 Transcription Factor; D053613:Janus Kinase 1
keywords: Azabenzimidazoles; JAK selectivity; JAK1; JAK1 inhibitors