title: Evaluation of 4,5,6,7-tetrahalogeno-1H-isoindole-1,3(2H)-diones as inhibitors of human protein kinase CK2.
abstract: Protein kinase CK2 (Casein Kinase 2) is an extremely pleiotropic Ser/Thr kinase with high constitutive activity. The observation of CK2 deregulations in various pathological processes suggests that CK2 inhibitors may have a therapeutic value, particularly as anti-neoplastic and antiviral drugs. Here, we present the 4,5,6,7-tetrahalogeno-1H-isoindole-1,3(2H)-diones as a novel potent class of CK2 inhibitors. We identified this class of inhibitors by high-throughput docking of a compound collection in the ATP-binding site of human CK2. The most active compounds are 2-(4,5,6,7-tetraiodo-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propanoic acid and 2-(4,5,6,7-tetraiodo-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)acetic acid with IC(50) values of 0.15 microM and 0.3 microM, respectively. These inhibitors are ATP-competitive and they only minimally inhibit the activities of protein kinases DYRK1a, MSK1, GSK3 and CDK5. Binding modes for the most active inhibitors are proposed.
authors.affiliation: Department of Combinatorial Chemistry, Institute of Molecular Biology and Genetics of National Academy of Sciences of Ukraine, Kyiv, Ukraine. andrew_golub@ukr.net
authors.forename: A G
authors.initials: AG
authors.lastname: Golub
authors.forename: O Ya
authors.initials: OY
authors.lastname: Yakovenko
authors.forename: A O
authors.initials: AO
authors.lastname: Prykhod'ko
authors.forename: S S
authors.initials: SS
authors.lastname: Lukashov
authors.forename: V G
authors.initials: VG
authors.lastname: Bdzhola
authors.forename: S M
authors.initials: SM
authors.lastname: Yarmoluk
mesh_terms: D001665:Binding Sites; D047390:Casein Kinase II / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D054833:Isoindoles / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D015394:Molecular Structure; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D011994:Recombinant Proteins
chemical_list: D054833:Isoindoles; D047428:Protein Kinase Inhibitors; D011994:Recombinant Proteins; D047390:Casein Kinase II