Synthesis and SAR of inhibitors of protein kinase CK2: Novel tricyclic quinoline analogs

Haddach, Mustapha; Pierre, Fabrice; Regan, B. C.; Borsan, Cosmin; Michaux, Jerome; Stefan, Eric; Kerdoncuff, Pauline; Schwaebe, Michael K.; Chua, Peter; Siddiqui‐Jain, Adam; Macalino, Diwata; Drygin, Denis; O’Brien, Sean; Rice, William G.; Ryckman, David M.

doi:10.1016/j.bmcl.2011.11.087

Cited by 16 publications

(12 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To further restrict our disruption to nucleolar integrity maintained by Pol I activity, we employed a second inhibitor, CX-5461, the first selective inhibitor of Pol I known to directly target the Pol I multienzyme complex [35]–[37]. Like Act-D, CX-5461 has also been shown to cause rapid nucleolar disruption in cell lines [38].…”

Section: Resultsmentioning

confidence: 99%

“…To assess the role of nucleoli in plasticity we disrupted nucleolar function in three ways: 1) 3-AB treatment which blocked regulated plasticity-dependent gene expression; 2) low-dose Act-D treatment which preferentially blocks transcriptional activity at GC–rich rDNA promoters; and 3) application of the highly specific Pol I inhibitor, CX-5461, which directly targets the Pol I multi-enzyme complex [35], [37], [38]. Each drug treatment was expected to directly and/or indirectly target ribosomal biogenesis through its rate limiting step, the production and maturation of rRNA.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Nucleolar Integrity Is Required for the Maintenance of Long-Term Synaptic Plasticity

et al. 2014

View full text Add to dashboard Cite

Long-term memory (LTM) formation requires new protein synthesis and new gene expression. Based on our work in Aplysia, we hypothesized that the rRNA genes, stimulation-dependent targets of the enzyme Poly(ADP-ribose) polymerase-1 (PARP-1), are primary effectors of the activity-dependent changes in synaptic function that maintain synaptic plasticity and memory. Using electrophysiology, immunohistochemistry, pharmacology and molecular biology techniques, we show here, for the first time, that the maintenance of forskolin-induced late-phase long-term potentiation (L-LTP) in mouse hippocampal slices requires nucleolar integrity and the expression of new rRNAs. The activity-dependent upregulation of rRNA, as well as L-LTP expression, are poly(ADP-ribosyl)ation (PAR) dependent and accompanied by an increase in nuclear PARP-1 and Poly(ADP) ribose molecules (pADPr) after forskolin stimulation. The upregulation of PARP-1 and pADPr is regulated by Protein kinase A (PKA) and extracellular signal-regulated kinase (ERK)—two kinases strongly associated with long-term plasticity and learning and memory. Selective inhibition of RNA Polymerase I (Pol I), responsible for the synthesis of precursor rRNA, results in the segmentation of nucleoli, the exclusion of PARP-1 from functional nucleolar compartments and disrupted L-LTP maintenance. Taken as a whole, these results suggest that new rRNAs (28S, 18S, and 5.8S ribosomal components)—hence, new ribosomes and nucleoli integrity—are required for the maintenance of long-term synaptic plasticity. This provides a mechanistic link between stimulation-dependent gene expression and the new protein synthesis known to be required for memory consolidation.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Nucleolar Integrity Is Required for the Maintenance of Long-Term Synaptic Plasticity

et al. 2014

View full text Add to dashboard Cite

show abstract

“…For the CX-4945 analogs, two crucial polar interactions exist simultaneously between the pyridine group and the carboxylate substituent with the hinge and positive regions, respectively. Haddach et al (34) synthesized a series of tricyclic quinoline analogs by changing the carboxylate group to a non-ionizable substituent and the carboxylate group at different positions, to investigate the function of the carboxylic acid at the R2 position on inhibitory activity. We built the three-dimensional quantitative structure-activity relationship (3D-QSAR) models for these types of compounds (35).…”

mentioning

confidence: 99%

Structural Basis for Low‐Affinity Binding of Non‐R2 Carboxylate‐Substituted Tricyclic Quinoline Analogs to CK2α: Comparative Molecular Dynamics Simulation Studies

Zhou

Zhang

et al. 2014

Chem Biol Drug Des

View full text Add to dashboard Cite

Protein kinase CK2 is a novel potential target for cancer treatment. The tricyclic quinoline compound CX-4945 (R2 = COOH) is the first bioavailable CK2 inhibitor used in human clinical trials for advanced solid tumors. CX-4945 analogs with non-R2 carboxylate function were demonstrated to be approximately 5000-fold less potent than compound 12 (R2 = COOH) in vitro. Molecular docking and molecular dynamics simulations were employed to elucidate the structural mechanisms through which the R2 non-ionizable and R3 carboxylic acid substituents influence binding affinity. Results show that the structure of CK2α and the orientation of ligands changed to different degrees in non-R2 carboxylate function systems. The inappropriate electrostatic interactions between the non-R2 carboxylate group and the positive region lead to improper protein-ligand recognition, which is followed by the reorientation of tricyclic skeletons. For CK2α, the affected positions are distributed over the glycine-rich loop (G-loop), C-loop, and the β4/β5 loop. The allosteric mechanisms between the deviated ligands and the changed regions are proposed. Detailed energy calculation and residue-based energy decomposition indicate the energetic influences on the contributions of the critical residues. These results are in accordance with one another and could provide rational clues to the design of more potent CK2 inhibitors.

show abstract

“…Our results suggest that MAF1 is a key transcription factor controlling tRNA transcription during DC activation. The involvement of CK2 in this process was tested using CX-4945, a specific inhibitor currently used in clinical trials (27,28). Immunoblotting for different targets of CK2 (AKT and eIF2β) was performed to confirm CX-4945's specificity in DCs (Fig.…”

Section: Resultsmentioning

confidence: 99%

Polymerase III transcription is necessary for T cell priming by dendritic cells

Reverendo

Argüello

Polte

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Exposure to microbe-associated molecular patterns (MAMPs) causes dendritic cells (DCs) to undergo a remarkable activation process characterized by changes in key biochemical mechanisms. These enhance antigen processing and presentation, as well as strengthen DC capacity to stimulate naïve T cell proliferation. Here, we show that in response to the MAMPS lipopolysaccharide and polyriboinosinic:polyribocytidylic acid (Poly I:C), RNA polymerase III (Pol lII)-dependent transcription and consequently tRNA gene expression are strongly induced in DCs. This is in part caused by the phosphorylation and nuclear export of MAF1 homolog negative regulator of Poll III (MAF1), via a synergistic casein kinase 2 (CK2)- and mammalian target of rapamycin-dependent signaling cascade downstream of Toll-like receptors (TLRs). De novo tRNA expression is necessary to augment protein synthesis and compensate for tRNA degradation driven by TLR-dependent DC exposure to type-I IFN. Although protein synthesis is not strongly inhibited in absence of RNA Pol III activity, it compromises the translation of key DC mRNAs, like those coding for costimulatory molecules and proinflammatory cytokines, which instead can be stored in stress granules, as shown for CD86 mRNA. TLR-dependent CK2 stimulation and subsequent RNA Pol III activation are therefore key for the acquisition by DCs of their unique T cell immune-stimulatory functions.

show abstract

Synthesis and SAR of inhibitors of protein kinase CK2: Novel tricyclic quinoline analogs

Cited by 16 publications

References 28 publications

Nucleolar Integrity Is Required for the Maintenance of Long-Term Synaptic Plasticity

Nucleolar Integrity Is Required for the Maintenance of Long-Term Synaptic Plasticity

Structural Basis for Low‐Affinity Binding of Non‐R2 Carboxylate‐Substituted Tricyclic Quinoline Analogs to CK2α: Comparative Molecular Dynamics Simulation Studies

Polymerase III transcription is necessary for T cell priming by dendritic cells

Contact Info

Product

Resources

About