title: SAR and evaluation of novel 5H-benzo[c][1,8]naphthyridin-6-one analogs as Aurora kinase inhibitors.
abstract: Several potent Aurora kinase inhibitors derived from 5H-benzo[c][1,8]naphthyridin-6-one scaffold were identified. A crystal structure of Aurora kinase A in complex with an initial hit revealed a binding mode of the inhibitor within the ATP binding site and provided insight for structure-guided compound optimization. Subsequent SAR campaign provided a potent and selective pan Aurora inhibitor, which demonstrated potent target modulation and antiproliferative effects in the pancreatic cell line, MIAPaCa-2. Furthermore, this compound inhibited phosphorylation of histone H3 (pHH3) in mouse bone morrow upon oral administration, which is consistent with inhibition of Aurora kinase B activity.
authors.affiliation: EMD Serono Research Institute, Inc., 45A Middlesex Turnpike, Billerica, MA 01821, United States. Srinivasa.karra@emdserono.com
authors.forename: Srinivasa
authors.initials: S
authors.lastname: Karra
authors.forename: Yufang
authors.initials: Y
authors.lastname: Xiao
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Chen
authors.forename: Lesley
authors.initials: L
authors.lastname: Liu-Bujalski
authors.forename: Bayard
authors.initials: B
authors.lastname: Huck
authors.forename: Amanda
authors.initials: A
authors.lastname: Sutton
authors.forename: Andreas
authors.initials: A
authors.lastname: Goutopoulos
authors.forename: Ben
authors.initials: B
authors.lastname: Askew
authors.forename: Kristopher
authors.initials: K
authors.lastname: Josephson
authors.forename: Xuliang
authors.initials: X
authors.lastname: Jiang
authors.forename: Adam
authors.initials: A
authors.lastname: Shutes
authors.forename: Vikram
authors.initials: V
authors.lastname: Shankar
authors.forename: Tom
authors.initials: T
authors.lastname: Noonan
authors.forename: Gaianne
authors.initials: G
authors.lastname: Garcia-Berrios
authors.forename: Rong
authors.initials: R
authors.lastname: Dong
authors.forename: Mohanraj
authors.initials: M
authors.lastname: Dhanabal
authors.forename: Hui
authors.initials: H
authors.lastname: Tian
authors.forename: Zhenxiong
authors.initials: Z
authors.lastname: Wang
authors.forename: A
authors.initials: A
authors.lastname: Clark
authors.forename: Samantha
authors.initials: S
authors.lastname: Goodstal
mesh_terms: D000284:Administration, Oral; D000818:Animals; D064127:Aurora Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D006657:Histones / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D009287:Naphthyridines / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: C584317:5H-benzo(c)(1,8)naphthyridin-6-one; D006657:Histones; D009287:Naphthyridines; D047428:Protein Kinase Inhibitors; D064127:Aurora Kinases