title: Development of Pharmacophore Model for Indeno[1,2-b]indoles as Human Protein Kinase CK2 Inhibitors and Database Mining.
abstract: Protein kinase CK2, initially designated as casein kinase 2, is an ubiquitously expressed serine/threonine kinase. This enzyme, implicated in many cellular processes, is highly expressed and active in many tumor cells. A large number of compounds has been developed as inhibitors comprising different backbones. Beside others, structures with an indeno[1,2-b]indole scaffold turned out to be potent new leads. With the aim of developing new inhibitors of human protein kinase CK2, we report here on the generation of common feature pharmacophore model to further explain the binding requirements for human CK2 inhibitors. Nine common chemical features of indeno[1,2-b]indole-type CK2 inhibitors were determined using MOE software (Chemical Computing Group, Montreal, Canada). This pharmacophore model was used for database mining with the aim to identify novel scaffolds for developing new potent and selective CK2 inhibitors. Using this strategy several structures were selected by searching inside the ZINC compound database. One of the selected compounds was bikaverin (6,11-dihydroxy-3,8-dimethoxy-1-methylbenzo[b]xanthene-7,10,12-trione), a natural compound which is produced by several kinds of fungi. This compound was tested on human recombinant CK2 and turned out to be an active inhibitor with an IC50value of 1.24 µM.
authors.affiliation: Institut für Pharmazeutische und Medizinische Chemie, PharmaCampus, Westfälische Wilhelms-Universität Münster, Corrensstr. 48, 48149 Münster, Germany. shaid_01@uni-muenster.de.|Faculty of Pharmacy, Damascus University, Damascus, P.O. Box 9411, Syria. shaid_01@uni-muenster.de.
authors.forename: Samer
authors.initials: S
authors.lastname: Haidar
authors.affiliation: Université de Lyon, Université Claude Bernard Lyon 1, Faculté de Pharmacie-ISPB, EA 4446 Bioactive Molecules and Medicinal Chemistry, SFR Santé Lyon-Est CNRS UMS3453-INSERM US7, 8 Avenue Rockefeller, F-69373 Lyon CEDEX 8, France. zouhair.bouaziz@univ-lyon1.fr.
authors.forename: Zouhair
authors.initials: Z
authors.lastname: Bouaziz
authors.affiliation: Université de Lyon, Université Claude Bernard Lyon 1, Faculté de Pharmacie-ISPB, EA 4446 Bioactive Molecules and Medicinal Chemistry, SFR Santé Lyon-Est CNRS UMS3453-INSERM US7, 8 Avenue Rockefeller, F-69373 Lyon CEDEX 8, France. christelle.marminon-davoust@univ-lyon1.fr.
authors.forename: Christelle
authors.initials: C
authors.lastname: Marminon
authors.affiliation: School of Pharmacy, Faculty of Health Sciences, University of Eastern, 70211 Kuopio, Finland. tuomo.laitinen@uef.fi.
authors.forename: Tuomo
authors.initials: T
authors.lastname: Laitinen
authors.affiliation: School of Pharmacy, Faculty of Health Sciences, University of Eastern, 70211 Kuopio, Finland. antti.poso@uef.fi.|University Hospital Tübingen, Department of Internal Medicine VIII, Otfried-Müller-Straβe 10, 72076 Tübingen, Germany. antti.poso@uef.fi.
authors.forename: Antti
authors.initials: A
authors.lastname: Poso
authors.affiliation: Université de Lyon, Université Claude Bernard Lyon 1, Faculté de Pharmacie-ISPB, EA 4446 Bioactive Molecules and Medicinal Chemistry, SFR Santé Lyon-Est CNRS UMS3453-INSERM US7, 8 Avenue Rockefeller, F-69373 Lyon CEDEX 8, France. marc.le-borgne@univ-lyon1.fr.
authors.forename: Marc
authors.initials: M
authors.lastname: Le Borgne
authors.affiliation: Institut für Pharmazeutische und Medizinische Chemie, PharmaCampus, Westfälische Wilhelms-Universität Münster, Corrensstr. 48, 48149 Münster, Germany. joachim.jose@uni-muenster.de.
authors.forename: Joachim
authors.initials: J
authors.lastname: Jose
keywords: CK2; MOE; ZINC database; cancer; indeno[1,2-b]indoles; pharmacophore