Structural basis of CX-4945 binding to human protein kinase CK2

Ferguson, Andrew D.; Sheth, Payal R.; Basso, Andrea; Paliwal, Sunil; Gray, Kimberly; Fischmann, Thierry O.; Le, Hung V.

doi:10.1016/j.febslet.2010.11.019

Cited by 110 publications

(127 citation statements)

References 29 publications

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“…Phase I clinical trials with the oral CK2 inhibitor CX-4945 (Cylene Pharmaceuticals; ref. 5) are ongoing in patients with multiple myeloma (trial number: NCT01199718).…”

Section: Introductionmentioning

confidence: 99%

Protein Kinase CK2 Protects Multiple Myeloma Cells from ER Stress–Induced Apoptosis and from the Cytotoxic Effect of HSP90 Inhibition through Regulation of the Unfolded Protein Response

Manni

Brancalion

Tubi

et al. 2012

Clinical Cancer Research

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Purpose: Protein kinase CK2 promotes multiple myeloma cell growth by regulating critical signaling pathways. CK2 also modulates proper HSP90-dependent client protein folding and maturation by phosphorylating its co-chaperone CDC37. Because the endoplasmic reticulum (ER) stress/unfolded protein response (UPR) is central in myeloma pathogenesis, we tested the hypothesis that the CK2/CDC37/HSP90 axis could be involved in UPR in myeloma cells.Experimental Design: We analyzed CK2 activity upon ER stress, the effects of its inactivation on the UPR pathways and on ER stress-induced apoptosis. The consequences of CK2 plus HSP90 inhibition on myeloma cell growth in vitro and in vivo and CK2 regulation of HSP90-triggered UPR were determined.Results: CK2 partly localized to the ER and ER stress triggered its kinase activity. CK2 inhibition reduced the levels of the ER stress sensors IRE1a and BIP/GRP78, increased phosphorylation of PERK and EIF2a, and enhanced ER stress-induced apoptosis. Simultaneous inactivation of CK2 and HSP90 resulted in a synergic anti-myeloma effect (combination index ¼ 0.291) and in much stronger alterations of the UPR pathways as compared with the single inhibition of the two molecules. Cytotoxicity from HSP90 and CK2 targeting was present in a myeloma microenvironment model, on plasma cells from patients with myeloma and in an in vivo mouse xenograft model. Mechanistically, CK2 inhibition led to a reduction of IRE1a/HSP90/CDC37 complexes in multiple myeloma cells.Conclusions: Our results place CK2 as a novel regulator of the ER stress/UPR cascades and HSP90 function in myeloma cells and offer the groundwork to design novel combination treatments for this disease.

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“…Phase I clinical trials with the oral CK2 inhibitor CX-4945 (Cylene Pharmaceuticals; ref. 5) are ongoing in patients with multiple myeloma (trial number: NCT01199718).…”

Section: Introductionmentioning

confidence: 99%

Protein Kinase CK2 Protects Multiple Myeloma Cells from ER Stress–Induced Apoptosis and from the Cytotoxic Effect of HSP90 Inhibition through Regulation of the Unfolded Protein Response

Manni

Brancalion

Tubi

et al. 2012

Clinical Cancer Research

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“…It is formed between the carboxyl oxygen of inhibitor and the side chain nitrogen of Lys68. It is worth to mention that this kind of interaction is observed in a number of small-molecule CK2 inhibitors [29][30][31][32][33] . Also, compound 7 forms additional hydrogen bond with Val116 in the hinge region of ATP-acceptor pocket.…”

Section: Resultsmentioning

confidence: 80%

Design, synthesis and biological evaluation of 2-aminopyrimidinones and their 6-aza-analogs as a new class of CK2 inhibitors

Chekanov

Ostrynska

Tarnavskyi

et al. 2013

Journal of Enzyme Inhibition and Medicinal Chemistry

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In order to find the new potent CK2 inhibitors the 60 derivatives of 2-aminopyrimidinone and their 6-aza-substituted analogs were synthesized and tested in vitro. Among them, the most efficient inhibitor 2-hydroxy-5-[4-(4-methoxyphehyl)-6-oxo-1,6-dihydropyrimidin-2-ylamino] benzoic acid was identified (IC 50 ¼ 1.1 mM). The structure-activity relationship study of newly synthesized derivatives was carried out and their binding mode with adenosine triphosphateacceptor site of CK2 was proposed.

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“…CX-4945, the most promising CK2α inhibitor, now in clinical trials) which are bound in a halogen bond-promoting mode, but distances between the halogen atom and proximal halogen bond acceptors are too long. Structural analysis demonstrates that in the complex of CX-4945 with CK2α, the small hydrophobic cavity is large enough to host not only chlorine [45], but also the larger bromine, or even iodine, attached to …”

Section: Discussionmentioning

confidence: 99%

Halogen bonding at the ATP binding site of protein kinases: Preferred geometry and topology of ligand binding

Poznański

Shugar

2013

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics

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Halogenated ligands have been widely developed as potent, and frequently selective, inhibitors of protein kinases (PK). Herein, all structures of protein kinases complexed with a halogenated ligand, identified in the PDB, were analyzed in the context of eventual contribution of halogen bonding to protein-ligand interactions. Global inspection shows that two carbonyl groups of residues located in the hinge region are the most abundant halogen bond acceptors. In contrast to solution data, well-defined water molecules, located at sites conserved across most PK structures, are also involved in halogen bonding. Analysis of cumulative distributions of halogen-acceptor distances shows that structures displaying short contacts involving a halogen atom are overpopulated, contributing together to clearly defined maxima of 2.82, 2.91 and 2.94 Å for chlorine, bromine and iodine, respectively. The angular preference of a halogen bond favors ideal topology (180°, 120°) for iodine. For bromine the distribution is much more dispersed, and no such preference was found for chlorine.

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Structural basis of CX-4945 binding to human protein kinase CK2

Cited by 110 publications

References 29 publications

Protein Kinase CK2 Protects Multiple Myeloma Cells from ER Stress–Induced Apoptosis and from the Cytotoxic Effect of HSP90 Inhibition through Regulation of the Unfolded Protein Response

Protein Kinase CK2 Protects Multiple Myeloma Cells from ER Stress–Induced Apoptosis and from the Cytotoxic Effect of HSP90 Inhibition through Regulation of the Unfolded Protein Response

Design, synthesis and biological evaluation of 2-aminopyrimidinones and their 6-aza-analogs as a new class of CK2 inhibitors

Halogen bonding at the ATP binding site of protein kinases: Preferred geometry and topology of ligand binding

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