AB668, a novel highly selective protein kinase CK2 inhibitor with a distinct anti-tumor mechanism as compared to CX-4945 and SGC-CK2-1

Bancet, Alexandre; Frem, Rita; Jeanneret, Florian; Mularoni, Angélique; Bazelle, Pauline; Roelants, Caroline; Delcros, Jean‐Guy; Guichou, Jean-François; Pillet, Catherine; Coste, Isabelle; Renno, Toufic; Battail, Christophe; Cochet, Claude; Lomberget, Thierry; Filhol, Odile; Krimm, Isabelle

doi:10.1101/2022.12.16.520736

Cited by 2 publications

(2 citation statements)

References 87 publications

(112 reference statements)

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“…AB668 was found to induce caspase-3 activation in clear cell renal cell carcinoma, elicit significant cell proliferation arrest in two cancer cell lines, and reduce cell viability in an ex vivo culture model of renal carcinoma. Assaying the CK2 activity in treated cell extracts has been used to indirectly assess the CK2 cellular target engagement of AB668 [28].…”

Section: Selected Allosteric and Bivalent Ck2 Inhibitors In Developmentmentioning

confidence: 99%

“…Through methods such as X-ray crystallography fragment screening and virtual screening, allosteric sites on CK2 capable of binding a small molecule have been identified [14,21]. These sites include the CK2α/CK2β interface [21][22][23][24] and the αD pocket [25][26][27][28], which is located near the CK2α (green and cyan) and two units of CK2β (red and yellow). CK2α may be substituted by CK2α' in physiological conditions.…”

Section: Introduction 1ck2 General Structure and Small Molecule Bindi...mentioning

confidence: 99%

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CK2 Chemical Probes: Past, Present, and Future

Ong,

Drewry,

Axtman

2023

Kinases and Phosphatases

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Protein kinase casein kinase 2 (CK2/CSNK2) is a pleiotropic kinase involved in many cellular processes and, accordingly, has been identified as a potential target for therapeutic intervention for multiple indications. Significant research effort has been invested into identifying CK2 inhibitors as potential drug candidates and potent and selective CK2 chemical probes to interrogate CK2 function. Here, we review the small molecule inhibitors reported for CK2 and discuss various orthosteric, allosteric, and bivalent inhibitors of CK2. We focus on the pyrazolo[1,5-a]pyrimidines and naphthyridines, two chemotypes that have been extensively explored for chemical probe development. We highlight the uptake and demonstrated utility of the pyrazolo[1,5-a]pyrimidine chemical probe SGC-CK2-1 by the scientific community in cellular studies. Finally, we propose criteria for an ideal in vivo chemical probe for investigating CK2 function in a living organism. While no compound currently meets these metrics, we discuss ongoing and future directions in the development of in vivo chemical probes for CK2.

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Section: Selected Allosteric and Bivalent Ck2 Inhibitors In Developmentmentioning

confidence: 99%

Section: Introduction 1ck2 General Structure and Small Molecule Bindi...mentioning

confidence: 99%

CK2 Chemical Probes: Past, Present, and Future

Ong,

Drewry,

Axtman

2023

Kinases and Phosphatases

View full text Add to dashboard Cite

show abstract

On Casein Kinase-2 (CK2) deregulation in NSCLC: an enzyme subunit-centered approach

Pérez,

Chen,

Chenyi

et al. 2023

Preprint

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CK2 is considered a constitutively active protein kinase promoting/supporting several neoplastic properties and inducing a so-called non-oncogene addiction in tumor cells. Compared to the extensive body of pre-clinical research, the translational and clinical information on CK2 is still limited. The holoenzyme, composed by a tetrameric array of two catalytic (CSNK2A1 and/or CSNK2A1) and two regulatory (CSNK2B) subunits, remains to be clinically validated. Herein, we interrogated available cancer multiomics databases to unravel CK2 deregulated expression in NSCLC. We focused our analysis on individual CK2 subunits assuming subunit-specific tumor supportive roles across cancers and particularly, within two major NSCLC subtypes. Moreover, we performed meta-analysis to uncover associations between CK2 expression and patient survival, as well as further correlations analysis with components of the tumor-microenvironment. The genomic and transcriptomic data analysis was complemented by IHC evaluation of CSNK2A1, CSNK2A2 and CSNK2B subunit expression, and CK2 enzymatic activity thereof. Overall, our data suggests that epigenetic, transcriptional and post-transcriptional regulatory mechanisms rather than mutational/gene amplification events may account for differential CK2 subunits expression/activity in NSCLC. Of note, CSNK2A1 and CSNK2B mRNA up-regulation consistently determine a worse patient prognosis in LUAD and correlated with increased infiltration of MDSCs/CAFs. Importantly, we corroborated that CK2 protein subunits levels and enzymatic activity are significantly exacerbated in LUAD and LUSC, but only CSNK2A1 positively correlated with tumor size and disease stage in the analyzed patient cohort, thus supporting our transcriptomic-based correlation analysis. Finally, we concluded that CSNK2A1 alone and/or the homo-tetramer thereof may be more instrumental to support NSCLC than CSNK2A2; thus, tailored drugs against these molecular CK2 entities may achieve better therapeutic windows at least for advanced lung cancer treatment.

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AB668, a novel highly selective protein kinase CK2 inhibitor with a distinct anti-tumor mechanism as compared to CX-4945 and SGC-CK2-1

Cited by 2 publications

References 87 publications

CK2 Chemical Probes: Past, Present, and Future

CK2 Chemical Probes: Past, Present, and Future

On Casein Kinase-2 (CK2) deregulation in NSCLC: an enzyme subunit-centered approach

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