title: Discovery of potent and highly selective thienopyridine Janus kinase 2 inhibitors.
abstract: Developing Janus kinase 2 (Jak2) inhibitors has become a significant focus for small molecule drug discovery programs in recent years due to the identification of a Jak2 gain-of-function mutation in the majority of patients with myeloproliferative disorders (MPD). Here, we describe the discovery of a thienopyridine series of Jak2 inhibitors that culminates with compounds showing 100- to >500-fold selectivity over the related Jak family kinases in enzyme assays. Selectivity for Jak2 was also observed in TEL-Jak cellular assays, as well as in cytokine-stimulated peripheral blood mononuclear cell (PBMC) and whole blood assays. X-ray cocrystal structures of 8 and 19 bound to the Jak2 kinase domain aided structure-activity relationship efforts and, along with a previously reported small molecule X-ray cocrystal structure of the Jak1 kinase domain, provided structural rationale for the observed high levels of Jak2 selectivity.
authors.affiliation: Department of Medicinal Chemistry, Amgen, Inc., 360 Binney Street, Cambridge, Massachusetts 02142, USA. laurie.schenkel@amgen.com
authors.forename: Laurie B
authors.initials: LB
authors.lastname: Schenkel
authors.forename: Xin
authors.initials: X
authors.lastname: Huang
authors.forename: Alan
authors.initials: A
authors.lastname: Cheng
authors.forename: Holly L
authors.initials: HL
authors.lastname: Deak
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Doherty
authors.forename: Renee
authors.initials: R
authors.lastname: Emkey
authors.forename: Yan
authors.initials: Y
authors.lastname: Gu
authors.forename: Hakan
authors.initials: H
authors.lastname: Gunaydin
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Kim
authors.forename: Josie
authors.initials: J
authors.lastname: Lee
authors.forename: Robert
authors.initials: R
authors.lastname: Loberg
authors.forename: Philip
authors.initials: P
authors.lastname: Olivieri
authors.forename: Jeanne
authors.initials: J
authors.lastname: Pistillo
authors.forename: Jin
authors.initials: J
authors.lastname: Tang
authors.forename: Qian
authors.initials: Q
authors.lastname: Wan
authors.forename: Hui-Ling
authors.initials: HL
authors.lastname: Wang
authors.forename: Shen-Wu
authors.initials: SW
authors.lastname: Wang
authors.forename: Mary C
authors.initials: MC
authors.lastname: Wells
authors.forename: Bin
authors.initials: B
authors.lastname: Wu
authors.forename: Violeta
authors.initials: V
authors.lastname: Yu
authors.forename: Liqin
authors.initials: L
authors.lastname: Liu
authors.forename: Stephanie
authors.initials: S
authors.lastname: Geuns-Meyer
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability; D018360:Crystallography, X-Ray; D006801:Humans; D053613:Janus Kinase 1 / Q000737:chemistry; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D007963:Leukocytes, Mononuclear / Q000187:drug effects; D008958:Models, Molecular; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship; D013552:Swine; D058924:Thienopyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D047428:Protein Kinase Inhibitors; D058924:Thienopyridines; D053613:Janus Kinase 1; D053614:Janus Kinase 2