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

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

doi:10.3390/ph10010008

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 IC50 value of 1.24 µM.

Highlights

Cancer remains the leading cause of death in the world and around eight million deaths related to cancer were reported worldwide in 2012
The radius of F1 and F3 were set at 0.8 A◦, F2 was set at 0.6 A◦, F4, F9 were set on 1 A◦, F5 was set on 0.4 A◦, F6 was set on 0.5 A◦, F7 and F8 were set on 0.7 A◦, and V1 was set on 1 A◦ (Figure 2).The pharmacophore search function of MOE was used to scan the test set using all default options of MOE
In this study we were able to valorize the library of indeno[1,2-b]indoles designed for CK2 inhibition to determine the necessary ligand binding requirement for ATP binding CK2 inhibitors

Summary

Introduction

Cancer remains the leading cause of death in the world and around eight million deaths related to cancer were reported worldwide in 2012. Different strategies for the treatment of cancer, including kinase inhibition [2] were employed and investigated to cure the disease or prolong life and increase its quality [3]. The first known protein kinase inhibitor was developed in the early 80s, and since a large number of compounds has been described (for reviews see [3,4]). The first protein kinase iPnhharimbaicteourticaaplsp2r0o17v, e1d0, 8as drug was imatinib (Gleevec® , Novartis), which is used in the treatme2not fo1f3 myelogenous leukemia [5]. [D9–if1fe3r].enSot mbaecokfbtohnoesse cwoemrepouusnedds atsursnkeedlettoonbefhorighAlTyPacctoivmepweittihtivICe 5C0 vKa2luienshiinbitthoersl,owamnoanngomthoelamr rinandgene.o[1,2-b]indoles have been identified as potent leads [8]. ZInINthCiscsotmudpyouanpdhadramtaabcaospeh[o2r0e].model for human protein kinase CK2 was constructed on the basis of 50 indeno[1,2-b]indoles and used to identify new hits by mining the ZINC compound database [20]

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Conclusion