Synthesis, biological properties and structural study of new halogenated azolo[4,5-b]pyridines as inhibitors of CK2 kinase

Chojnacki, Konrad; Lindenblatt, D.; Wińska, Patrycja; Wielechowska, Monika; Toelzer, Christine; Niefind, Karsten; Bretner, Maria

doi:10.1016/j.bioorg.2020.104502

Cited by 14 publications

(17 citation statements)

References 59 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Additionally, molecular docking of 2 and 5 to human CK2α (PDB: 7A4C [63]) was performed (for details, see Supplementary Materials, Figure S2) and binding modes were proposed. Both inhibitors bind similarly in the active site of CK2α with a similar docking score concerning binding affinity energies expressed as ∆G calc (kcal/mol) (-7.0 for 2 and -7.1 for 5).…”

Section: Biological Evaluation 221 Inhibition Of Recombinant Ck2 and Pim1mentioning

confidence: 99%

Synthesis of Novel Acyl Derivatives of 3-(4,5,6,7-Tetrabromo-1H-benzimidazol-1-yl)propan-1-ols—Intracellular TBBi-Based CK2 Inhibitors with Proapoptotic Properties

Chojnacki

Wińska

Karatsai

et al. 2021

IJMS

View full text Add to dashboard Cite

Protein kinase CK2 has been considered as an attractive drug target for anti-cancer therapy. The synthesis of N-hydroxypropyl TBBi and 2MeTBBi derivatives as well as their respective esters was carried out by using chemoenzymatic methods. Concomitantly with kinetic studies toward recombinant CK2, the influence of the obtained compounds on the viability of two human breast carcinoma cell lines (MCF-7 and MDA-MB-231) was evaluated using MTT assay. Additionally, an intracellular inhibition of CK2 as well as an induction of apoptosis in the examined cells after the treatment with the most active compounds were studied by Western blot analysis, phase-contrast microscopy and flow cytometry method. The results of the MTT test revealed potent cytotoxic activities for most of the newly synthesized compounds (EC50 4.90 to 32.77 µM), corresponding to their solubility in biological media. We concluded that derivatives with the methyl group decrease the viability of both cell lines more efficiently than their non-methylated analogs. Furthermore, inhibition of CK2 in breast cancer cells treated with the tested compounds at the concentrations equal to their EC50 values correlates well with their lipophilicity since derivatives with higher values of logP are more potent intracellular inhibitors of CK2 with better proapoptotic properties than their parental hydroxyl compounds.

show abstract

Section: Biological Evaluation 221 Inhibition Of Recombinant Ck2 and Pim1mentioning

confidence: 99%

Synthesis of Novel Acyl Derivatives of 3-(4,5,6,7-Tetrabromo-1H-benzimidazol-1-yl)propan-1-ols—Intracellular TBBi-Based CK2 Inhibitors with Proapoptotic Properties

Chojnacki

Wińska

Karatsai

et al. 2021

IJMS

View full text Add to dashboard Cite

show abstract

“…The two water molecules interacting solely with the pyridine and triazole nitrogen atom of the ligand provide a possible explanation for the substantial gain in affinity when replacing these nitrogen atoms in the analogous set. A similar binding mode has been described for 5,6-dibromopyridinotriazole with CK2α and CK2α′ forming similar interactions with the ATP pocket. , With DYRK1a, very similar azaindole inhibitors have been described, but they all feature sophisticated hydrogen bond networks with the hinge region …”

Section: Resultsmentioning

confidence: 70%

“…A similar binding mode has been described for 5,6-dibromopyridinotriazole with CK2α and CK2α′ forming similar interactions with the ATP pocket. 43,47 With DYRK1a, very similar azaindole inhibitors have been described, but they all feature sophisticated hydrogen bond networks with the hinge region. 35 The second observed binding mode showcases more enthalpic interactions than the ATP-competitive one (Figure 4c).…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Screening of a Halogen-Enriched Fragment Library Leads to Unconventional Binding Modes

et al. 2022

View full text Add to dashboard Cite

We conceived the Halogen-Enriched Fragment Library (HEFLib) to investigate the potential of halogen bonds in the early stages of drug discovery. As the number of competitive interactions increases with ligand size, we reasoned that a binding mode relying on halogen bonding is more likely for fragments than highly decorated molecules. Thus, fragments could feature unexplored binding modes. We screened the HEFLib against the human kinase DYRK1a and verified micromolar binding fragments via isothermal titration calorimetry (ITC). The crystal structure of one fragment revealed a noncanonical binding mode, despite the fragment’s classical hinge binding motif. In addition, the fragment occupies a secondary binding site. Both binding modes feature a halogen bond, which we evaluated by ab initio calculations. Structure–affinity relationship (SAR) from a set of analogues improves the affinity, provides a promising fragment-growth vector, and highlights the benefits and applicability of halogen bonds in early lead development.

show abstract

“…It depends on crystals of the oxidation-stable mutant CK2α′ Cys336Ser (Figure S1) in complex with the ATP site ligand MB002 (Figure d) that is subsequently exchanged by extensive soaking . The method was successful with CX-4945 and with several other high-, medium-, and low-affinity ATP-competitive ligands, ,, but it was unclear if it works for allosteric sites, as well. A first study to explore this failed insofar as it proved that certain 2-aminothiazole compounds described before to be allosteric CK2 inhibitors actually bind to the ATP site …”

Section: Results and Discussionmentioning

confidence: 99%

Molecular Plasticity of Crystalline CK2α′ Leads to KN2, a Bivalent Inhibitor of Protein Kinase CK2 with Extraordinary Selectivity

et al. 2021

View full text Add to dashboard Cite

CK2α and CK2α′ are paralogous catalytic subunits of CK2, which belongs to the eukaryotic protein kinases. CK2 promotes tumorigenesis and the spread of pathogenic viruses like SARS-CoV-2 and is thus an attractive drug target. Efforts to develop selective CK2 inhibitors binding offside the ATP site had disclosed the αD pocket in CK2α; its occupation requires large conformational adaptations of the helix αD. As shown here, the αD pocket is accessible also in CK2α′, where the necessary structural plasticity can be triggered with suitable ligands even in the crystalline state. A CK2α′ structure with an ATP site and an αD pocket ligand guided the design of the bivalent CK2 inhibitor KN2. It binds to CK2 with low nanomolar affinity, is cell-permeable, and suppresses the intracellular phosphorylation of typical CK2 substrates. Kinase profiling revealed a high selectivity of KN2 for CK2 and emphasizes the selectivity-promoting potential of the αD pocket.

show abstract

Synthesis, biological properties and structural study of new halogenated azolo[4,5-b]pyridines as inhibitors of CK2 kinase

Cited by 14 publications

References 59 publications

Synthesis of Novel Acyl Derivatives of 3-(4,5,6,7-Tetrabromo-1H-benzimidazol-1-yl)propan-1-ols—Intracellular TBBi-Based CK2 Inhibitors with Proapoptotic Properties

Synthesis of Novel Acyl Derivatives of 3-(4,5,6,7-Tetrabromo-1H-benzimidazol-1-yl)propan-1-ols—Intracellular TBBi-Based CK2 Inhibitors with Proapoptotic Properties

Screening of a Halogen-Enriched Fragment Library Leads to Unconventional Binding Modes

Molecular Plasticity of Crystalline CK2α′ Leads to KN2, a Bivalent Inhibitor of Protein Kinase CK2 with Extraordinary Selectivity

Contact Info

Product

Resources

About