title: Isoxazolo[3,4-b]quinoline-3,4(1H,9H)-diones as unique, potent and selective inhibitors for Pim-1 and Pim-2 kinases: chemistry, biological activities, and molecular modeling.
abstract: A series of isoxazolo[3,4-b]quinoline-3,4(1H,9H)-diones were synthesized as potent inhibitors against Pim-1 and Pim-2 kinases. The structure-activity-relationship studies started from a high-throughput screening hit and was guided by molecular modeling of inhibitors in the active site of Pim-1 kinase. Installing a hydroxyl group on the benzene ring of the core has the potential to form a key hydrogen bond interaction to the hinge region of the binding pocket and thus resulted in the most potent inhibitor, 19, with K(i) values at 2.5 and 43.5 nM against Pim-1 and Pim-2, respectively. Compound 19 also exhibited an activity profile with a high degree of kinase selectivity.
authors.affiliation: Cancer Research, Global Pharmaceutical R&D, Abbott Laboratories, R47S, AP10, 100 Abbott Park Road, Abbott Park, IL 60064, USA. yunsong.tong@abbott.com
authors.forename: Yunsong
authors.initials: Y
authors.lastname: Tong
authors.forename: Kent D
authors.initials: KD
authors.lastname: Stewart
authors.forename: Sheela
authors.initials: S
authors.lastname: Thomas
authors.forename: Magdalena
authors.initials: M
authors.lastname: Przytulinska
authors.forename: Eric F
authors.initials: EF
authors.lastname: Johnson
authors.forename: Vered
authors.initials: V
authors.lastname: Klinghofer
authors.forename: Joel
authors.initials: J
authors.lastname: Leverson
authors.forename: Owen
authors.initials: O
authors.lastname: McCall
authors.forename: Niru B
authors.initials: NB
authors.lastname: Soni
authors.forename: Yan
authors.initials: Y
authors.lastname: Luo
authors.forename: Nan-horng
authors.initials: NH
authors.lastname: Lin
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Sowin
authors.forename: Vincent L
authors.initials: VL
authors.lastname: Giranda
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Penning
mesh_terms: D020650:Combinatorial Chemistry Techniques; D018360:Crystallography, X-Ray; D006801:Humans; D007555:Isoxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors*; D051573:Proto-Oncogene Proteins c-pim-1 / Q000037:antagonists & inhibitors*; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D007555:Isoxazoles; C490587:PIM2 protein, human; D011518:Proto-Oncogene Proteins; D011804:Quinolines; C496634:PIM1 protein, human; D017346:Protein Serine-Threonine Kinases; D051573:Proto-Oncogene Proteins c-pim-1