Novel non-ATP competitive small molecules targeting the CK2 α/β interface

Brear, P.; North, Andrew J. P.; Iegre, Jessica; Georgiou, K.H.; Lubin, Alexandra; Carro, L.; Green, William; Sore, Hannah F.; Hyvönen, Marko; Spring, David R.

doi:10.1016/j.bmc.2018.05.011

Cited by 38 publications

(32 citation statements)

References 24 publications

(48 reference statements)

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“…Very recently, the non‐ATP‐competitive ligand CAM187 ( 2 , Figure ) was reported to bind to the CK2α subunit and inhibit the interaction with the CK2β subunit (IC 50 =44 μM). Although 2 was able to affect this PPI, it did not significantly inhibit CK2 activity . The same behavior was observed for the cyclic 13 amino acid peptide Pc and its derivatives, which were designed as CK2β mimetics to inhibit CK2 subunit association …”

Section: Introductionsupporting

confidence: 56%

Synthesis and SAR of Tetracyclic Inhibitors of Protein Kinase CK2 Derived from Furocarbazole W16

et al. 2020

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The serine/threonine kinase CK2 modulates the activity of more than 300 proteins and thus plays a crucial role in various physiological and pathophysiological processes including neurodegenerative disorders of the central nervous system and cancer. The enzymatic activity of CK2 is controlled by the equilibrium between the heterotetrameric holoenzyme CK2α 2 β 2 and its monomeric subunits CK2α and CK2β. A series of) was prepared in an one-pot, three-component Levy reaction. The stereochemistry of the tetracyclic compounds was analyzed. Additionally, the chemically labile anhydride structure of the furocarbazoles 3 was replaced by a more stable imide (9) and N-methylimide (10) substructure. The enantiomer (À )-3 a (K i = 4.9 μM) of the lead compound (+)-3 a (K i = 31 μM) showed a more than sixfold increased inhibition of the CK2α/CK2β interaction (protein-protein interaction inhibition, PPII) in a microscale thermophoresis (MST) assay. However, (À )-3 a did not show an increased enzyme inhibition of the CK2α 2 β 2 holoenzyme, the CK2α subunit or the mutated CK2α' C336S subunit in the capillary electrophoresis assay. In the pyrrolocarbazole series, the imide (À )-9 a (K i = 3.6 μM) and the N-methylimide (+)-10 a (K i = 2.8 μM) represent the most promising inhibitors of the CK2α/CK2β interaction. However, neither compound could inhibit enzymatic activity. Unexpectedly, the racemic tetracyclic pyrrolocarbazole (�)-12, with a carboxy moiety in the 4-position, displays the highest CK2α/CK2β interaction inhibition (K i = 1.8 μM) of this series of compounds.

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Section: Introductionsupporting

confidence: 56%

Synthesis and SAR of Tetracyclic Inhibitors of Protein Kinase CK2 Derived from Furocarbazole W16

et al. 2020

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“…Non-peptidic antagonists of the CK2a/CK2b interaction were describeds of ar three times, [59][60][61] but in no case with cell culture studies so that the efficacy of such compounds in ap hys-iologicale nvironment remains to be shown. Vice versa, cellular data (albeit without ad istinction between cancera nd noncancer cells), but no enzymological results were included in a study [39] with in silico designed Pc variants coupledt oaT AT sequencea sc ell-penetrating peptide.…”

Section: Synthesis Of Pc Derivatives and Characterization With Humanmentioning

confidence: 99%

Design of CK2β‐Mimicking Peptides as Tools To Study the CK2α/CK2β Interaction in Cancer Cells

et al. 2019

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The ubiquitously expressed Ser/Thr kinase CK2 is a key regulator in a variety of key processes in normal and malignant cells. Due to its distinctive anti‐apoptotic and tumor‐driving properties, elevated levels of CK2 have frequently been found in tumors of different origin. In recent years, development of CK2 inhibitors has largely been focused on ATP‐competitive compounds; however, targeting the CK2α/CK2β interface has emerged as a further concept that might avoid selectivity issues. To address the CK2 subunit interaction site, we have synthesized halogenated CK2β‐mimicking cyclic peptides modified with the cell‐penetrating peptide sC18 to mediate cellular uptake. We investigated the binding of the resulting chimeric peptides to recombinant human CK2α using a recently developed fluorescence anisotropy assay. The iodinated peptide sC18‐I‐Pc was identified as a potent CK2α ligand (Ki=0.622 μm). It was internalized in cells to a high extent and exhibited significant cytotoxicity toward cancerous HeLa cells (IC50=37 μm) in contrast to non‐cancerous HEK‐293 cells. The attractive features and functionalities of sC18‐I‐Pc offer the opportunity for further improvement.

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“…To date, three kinds of allosteric inhibitors were reported (show in Figure 1). CK2 α/β interface (Site 6 including Tyr 39, Val67, Val112 and Val101) has been confirmed to be occupied by the DRB, W16, CAM187 and cyclic peptide Pc, which antagonize the assembly of CK2 holoenzyme complex [16]. The αD pocket named site 3 was demonstrated as the allosteric pocket to accommodate the biaryl rings of CAM4712 analogues [17][18][19].…”

Section: Introductionmentioning

confidence: 89%

Identification and Biological Evaluation of CK2 Allosteric Fragments through Structure-Based Virtual Screening

Zhang

et al. 2020

Molecules

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Casein kinase II (CK2) is considered as an attractive cancer therapeutic target, and recent efforts have been made to develop its ATP-competitive inhibitors. However, achieving selectivity with respect to related kinases remains challenging due to the highly conserved ATP-binding pocket of kinases. Allosteric inhibitors, by targeting the much more diversified allosteric site relative to the highly conserved ATP-binding pocket, might be a promising strategy with the enhanced selectivity and reduced toxicity than ATP-competitive inhibitors. The previous studies have highlighted the traditional serendipitousity of discovering allosteric inhibitors owing to the complicate allosteric modulation. In this current study, we identified the novel allosteric inhibitors of CK2α by combing structure-based virtual screening and biological evaluation methods. The structure-based pharmacophore model was built based on the crystal structure of CK2α-compound 15 complex. The ChemBridge fragment library was searched by evaluating the fit values of these molecules with the optimized pharmacophore model, as well as the binding affinity of the CK2α-ligand complexes predicted by Alloscore web server. Six hits forming the holistic interaction mechanism with the αD pocket were retained after pharmacophore- and Alloscore-based screening for biological test. Compound 3 was found to be the most potent non-ATP competitive CK2α inhibitor (IC50 = 13.0 μM) with the anti-proliferative activity on A549 cancer cells (IC50 = 23.1 μM). Our results provide new clues for further development of CK2 allosteric inhibitors as anti-cancer hits.

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Novel non-ATP competitive small molecules targeting the CK2 α/β interface

Cited by 38 publications

References 24 publications

Synthesis and SAR of Tetracyclic Inhibitors of Protein Kinase CK2 Derived from Furocarbazole W16

Synthesis and SAR of Tetracyclic Inhibitors of Protein Kinase CK2 Derived from Furocarbazole W16

Design of CK2β‐Mimicking Peptides as Tools To Study the CK2α/CK2β Interaction in Cancer Cells

Identification and Biological Evaluation of CK2 Allosteric Fragments through Structure-Based Virtual Screening

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