title: Design and evaluation of novel 8-oxo-pyridopyrimidine Jak1/2 inhibitors.
abstract: A highly ligand efficient, novel 8-oxo-pyridopyrimidine containing inhibitor of Jak1 and Jak2 isoforms with a pyridone moiety as the hinge-binding motif was discovered. Structure-based design strategies were applied to significantly improve enzyme potency and the polarity of the molecule was adjusted to gain cellular activity. The crystal structures of two representative inhibitors bound to Jak1 were obtained to enable SAR exploration.
authors.affiliation: Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA. Electronic address: sharadal@gene.com.
authors.forename: Sharada
authors.initials: S
authors.lastname: Labadie
authors.forename: Kathy
authors.initials: K
authors.lastname: Barrett
authors.forename: Wade S
authors.initials: WS
authors.lastname: Blair
authors.forename: Christine
authors.initials: C
authors.lastname: Chang
authors.forename: Gauri
authors.initials: G
authors.lastname: Deshmukh
authors.forename: Charles
authors.initials: C
authors.lastname: Eigenbrot
authors.forename: Paul
authors.initials: P
authors.lastname: Gibbons
authors.forename: Adam
authors.initials: A
authors.lastname: Johnson
authors.forename: Jane R
authors.initials: JR
authors.lastname: Kenny
authors.forename: Pawan Bir
authors.initials: PB
authors.lastname: Kohli
authors.forename: Marya
authors.initials: M
authors.lastname: Liimatta
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Lupardus
authors.forename: Steven
authors.initials: S
authors.lastname: Shia
authors.forename: Micah
authors.initials: M
authors.lastname: Steffek
authors.forename: Savita
authors.initials: S
authors.lastname: Ubhayakar
authors.forename: Anne
authors.initials: A
authors.lastname: van Abbema
authors.forename: Mark
authors.initials: M
authors.lastname: Zak
mesh_terms: D006801:Humans; D053613:Janus Kinase 1 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D062105:Molecular Docking Simulation; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D011743:Pyrimidines / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D053613:Janus Kinase 1; D053614:Janus Kinase 2
keywords: 8-Oxo-pyridopyrimidines; Hematopoiesis; JAK inhibitors; Rheumatoid arthritis