Development of Pharmacophore Model for Indeno[1,2-b]indoles as Human Protein Kinase CK2 Inhibitors and Database Mining

Samer Haidar (1) , Zouhair Bouaziz (2) , Christelle Marminon (2) , Tuomo Laitinen , Antti Poso , Marc Le Borgne (2) , Joachim Jose (1)

1 WWU - Westfälische Wilhelms-Universität Münster = University of Münster
2 B2MC - Molécules bioactives et chimie médicinale

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 IC 50 value of 1.24 µM.

Mots clés: ZINC database; MOE; pharmacophore; indeno[1; 2-b]indoles; cancer; CK2

Domaines: Chimie thérapeutique; Chemo-informatique; Sciences pharmaceutiques; Cancer

Samer Haidar, Zouhair Bouaziz, Christelle Marminon, Tuomo Laitinen, Antti Poso, et al.. Development of Pharmacophore Model for Indeno[1,2-b]indoles as Human Protein Kinase CK2 Inhibitors and Database Mining. Pharmaceuticals, 2017, An Updated View on an Emerging Target: Selected Papers from the 8th International Conference on Protein Kinase CK2, 10 ((1)8), ⟨10.3390/ph10010008⟩. ⟨hal-01683291⟩