Antitumoral activity of allosteric inhibitors of protein kinase CK2

Abstract

IntroductionDue to its physiological role into promoting cell survival and its dysregulation in most cancer cells, protein kinase CK2 is a relevant physiopathological target for development of chemical inhibitors. We report the discovery of azonaphthalene derivatives, as a new family of highly specific CK2 inhibitors. First, we demonstrated that CK2 inhibition (IC50= 0.4 μM) was highly specific, reversible and non ATP-competitive. Small Angle X-ray Scattering experiments showed that this inhibition was due to large conformational change of CK2α upon binding of these inhibitors. We showed that several compounds of the family were cell-potent CK2 inhibitors promoting cell cycle arrest of human glioblastoma U373 cells. Finally, in vitro and in vivo assays showed that these compounds could decrease U373 cell tumor mass by 83% emphasizing their efficacy against these apoptosis-resistant tumors. In contrast, Azonaphthalene derivatives inactive on CK2 activity showed no effect in colony formation and tumor regression assays. These findings illustrate the emergence of nonclassical CK2 inhibitors and provide exciting opportunities for the development of novel allosteric CK2 inhibitors.BackgroundCK2 is an emerging therapeutic target and ATP-competitive inhibitors have been identified. CK2 is endowed with specific structural features providing alternative strategies for inhibition.ResultsAzonaphthalene compounds are allosteric CK2 inhibitors showing antitumor activity.ConclusionCK2 may be targeted allosterically.SignificanceThese inhibitors provide a foundation for a new paradigm for specific CK2 inhibition.

CK2 inhibition induced PDK4-AMPK axis regulates metabolic adaptation and survival responses in glioma

“…CK2 is being regarded as an emerging anti-tumor therapeutic target [18], and CK2 inhibition suppresses prosurvival signaling pathways and growth of glioblastoma [19]. Since metabolism, senescence and survival of cancer cells are intricately connected, and as possible initiation of clinical trials using CK2 antagonists in chronic lymphocytic leukemia holds promise [20]; we studied the effect of CK2 inhibition on the metabolic adaptation in glioma cells and its consequences on the survival of these cells, in both in vitro and in vivo mouse xenograft model of glioma.…”

Force et spécificité du criblage pour des molécules bioactives au CMBA-Grenoble

“…La faculté de bloquer simultanément CK2 et PIM dans ce type de cancers est donc particulièrement intéressante [6]. Des dérivés des azonaphatalènes, qui induisent un changement de conformation de type allostérique après leur fixation sur CK2, se montrent efficaces dans un modèle de xénogreffes de glioblastome [4]. Les polyoxométalates (POM), quant à eux, sont des agrégats nanométriques anioniques de métaux de transition (vanadium, molybdène, tungstène).…”

“…TAMIS évolue continuellement, notamment pour l'inté-gration de méthodes d'analyses statistiques innovantes dédiées à l'analyse des résultats de HTS et HCS ; ces méthodes ont été développées en collaboration avec le Pr R. Nadon de l'Université de Montréal [32][33][34][35]. 4 Groupe informatique pour le sud-est.…”

“…Utilisés quotidiennement en laboratoire, les tests et le savoir-faire des chercheurs constituent une ressource largement sous exploitée pour le criblage et la découverte de molécules bioactives. Le champ d'application de ces molécules ne se limite pas au secteur du médicament : les molécules chimiques découvertes au centre de criblage pour des molécules bioactives du CEA-Grenoble (CMBA-Grenoble) se révèlent des outils prometteurs tant en recherche fondamentale [3][4][5][6][7][8][9] que pour des applications dans les domaines de la santé 2 , de l'environnement ou des bioénergies 3 .…”

In vivo siRNA distribution and pharmacokinetics assessed by nuclear imaging are modulated according to radiolabelling site

“…It has been reported that deregulation of CK2 activity could be linked to the development of human cancers [18], and that its up-regulation has been described in glioblastomas [19]. Moreover, CK2 inhibition has been shown to have anti-tumor effect in human-glioblastoma xenografts [19,20]. In this study, we used an siRNA targeting the beta subunit of CK2 (CK2β), previously reported to inhibit at least 70% of CK2β activity [21].…”