16 results on '"Golub, Andriy G."'
Search Results
2. Design and synthesis of novel protein kinase CK2 inhibitors on the base of 4-aminothieno[2,3-d]pyrimidines.
- Author
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Ostrynska OV, Balanda AO, Bdzhola VG, Golub AG, Kotey IM, Kukharenko OP, Gryshchenko AA, Briukhovetska NV, and Yarmoluk SM
- Subjects
- Casein Kinase II metabolism, Dose-Response Relationship, Drug, Humans, Models, Molecular, Molecular Structure, Protein Kinase Inhibitors chemical synthesis, Protein Kinase Inhibitors chemistry, Pyrimidines chemical synthesis, Pyrimidines chemistry, Structure-Activity Relationship, Casein Kinase II antagonists & inhibitors, Drug Design, Protein Kinase Inhibitors pharmacology, Pyrimidines pharmacology
- Abstract
An extension of our previous research work has resulted in a number of new ATP-competitive CK2 inhibitors that have been identified among 4-aminothieno[2,3-d]pyrimidine derivatives. The most active compounds obtained in the course of the research are 3-(5-p-tolyl-thieno[2,3-d]pyrimidin-4-ylamino)-benzoic acid, 5e (NHTP23, IC50 = 0.01 μM), 3-(5-phenyl-thieno[2,3-d]pyrimidin-4-ylamino)-benzoic acid, 5g (NHTP25, IC50 = 0.065 μM) and 3-(6-methyl-5-phenyl-thieno[2,3-d]pyrimidin-4-ylamino)-benzoic acid, 5n (NHTP33, IC50 = 0.008 μM). Structure-activity relationships of the tested 4-aminothieno[2,3-d]pyrimidine derivatives have been studied and their binding mode with ATP-acceptor site of CK2 has been proposed. A negative effect of intramolecular hydrogen bonding in the compounds' structure is discussed., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)
- Published
- 2016
- Full Text
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3. Discovery of potent anti-tuberculosis agents targeting leucyl-tRNA synthetase.
- Author
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Gudzera OI, Golub AG, Bdzhola VG, Volynets GP, Lukashov SS, Kovalenko OP, Kriklivyi IA, Yaremchuk AD, Starosyla SA, Yarmoluk SM, and Tukalo MA
- Subjects
- Amino Acid Sequence, Enzyme Inhibitors chemistry, Enzyme Inhibitors pharmacology, Humans, Leucine-tRNA Ligase chemistry, Leucine-tRNA Ligase metabolism, Models, Molecular, Molecular Sequence Data, Mycobacterium tuberculosis chemistry, Nitrophenols chemical synthesis, Nitrophenols chemistry, Nitrophenols pharmacology, Protein Structure, Tertiary, Sequence Alignment, Tuberculosis microbiology, Antitubercular Agents chemistry, Antitubercular Agents pharmacology, Leucine-tRNA Ligase antagonists & inhibitors, Mycobacterium tuberculosis drug effects, Mycobacterium tuberculosis enzymology, Tuberculosis drug therapy
- Abstract
Tuberculosis is a serious infectious disease caused by human pathogen bacteria Mycobacterium tuberculosis. Bacterial drug resistance is a very significant medical problem nowadays and development of novel antibiotics with different mechanisms of action is an important goal of modern medical science. Leucyl-tRNA synthetase (LeuRS) has been recently clinically validated as antimicrobial target. Here we report the discovery of small-molecule inhibitors of M. tuberculosis LeuRS. Using receptor-based virtual screening we have identified six inhibitors of M. tuberculosis LeuRS from two different chemical classes. The most active compound 4-{[4-(4-Bromo-phenyl)-thiazol-2-yl]hydrazonomethyl}-2-methoxy-6-nitro-phenol (1) inhibits LeuRS with IC50 of 6μM. A series of derivatives has been synthesized and evaluated in vitro toward M. tuberculosis LeuRS. It was revealed that the most active compound 2,6-Dibromo-4-{[4-(4-nitro-phenyl)-thiazol-2-yl]-hydrazonomethyl}-phenol inhibits LeuRS with IC50 of 2.27μM. All active compounds were tested for antimicrobial effect against M. tuberculosis H37Rv. The compound 1 seems to have the best cell permeability and inhibits growth of pathogenic bacteria with IC50=10.01μM and IC90=13.53μM., (Copyright © 2016 Elsevier Ltd. All rights reserved.)
- Published
- 2016
- Full Text
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4. Identification of Mycobacterium tuberculosis leucyl-tRNA synthetase (LeuRS) inhibitors among the derivatives of 5-phenylamino-2H-[1,2,4]triazin-3-one.
- Author
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Gudzera OI, Golub AG, Bdzhola VG, Volynets GP, Kovalenko OP, Boyarshin KS, Yaremchuk AD, Protopopov MV, Yarmoluk SM, and Tukalo MA
- Subjects
- Anti-Bacterial Agents analysis, Anti-Bacterial Agents isolation & purification, Dose-Response Relationship, Drug, Humans, Inhibitory Concentration 50, Leucine-tRNA Ligase metabolism, Molecular Docking Simulation, Molecular Structure, Structure-Activity Relationship, Triazines chemical synthesis, Triazines chemistry, Anti-Bacterial Agents chemistry, Anti-Bacterial Agents pharmacology, Leucine-tRNA Ligase antagonists & inhibitors, Mycobacterium tuberculosis drug effects, Mycobacterium tuberculosis enzymology, Triazines pharmacology
- Abstract
The increase of antibiotic resistance amongst Mycobacterium tuberculosis strains has become one of the most pressing problems of modern medicine. Therefore, the search of antibiotics against M. tuberculosis with novel mechanisms of action is very important. We have identified inhibitors of M. tuberculosis leucyl-tRNA synthetase (LeuRS) among the derivatives of 5-phenylamino-2H-[1,2,4]triazin-3-one. The most active compounds 5-(5-chloro-2-hydroxy-phenylamino)-6-methyl-2H-[1,2,4]triazin-3-one and 5-(5-chloro-2-hydroxy-phenylamino)-2H-[1,2,4]triazin-3-one inhibit M. tuberculosis LeuRS with IC
50 of 7.6 μМ and 7.2 μМ, respectively. It was established that the inhibitory activity of compounds against pathogenic LeuRS is 10-fold better, than for human enzyme.- Published
- 2016
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5. A Note of Caution on the Role of Halogen Bonds for Protein Kinase/Inhibitor Recognition Suggested by High- And Low-Salt CK2α Complex Structures.
- Author
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Guerra B, Bischoff N, Bdzhola VG, Yarmoluk SM, Issinger OG, Golub AG, and Niefind K
- Subjects
- Adenosine Triphosphate metabolism, Casein Kinase II antagonists & inhibitors, Casein Kinase II chemistry, Casein Kinase II metabolism, Catalytic Domain, Crystallography, X-Ray, Halogenation, Humans, Molecular Docking Simulation, Protein Conformation, Protein Structure, Secondary, Salts chemistry, Protein Kinase Inhibitors chemistry, Protein Kinase Inhibitors pharmacology
- Abstract
CK2 is a Ser/Thr kinase recruited by tumor cells to avoid cell death. 4'-Carboxy-6,8-dibromo-flavonol (FLC26) is a nanomolar CK2 inhibitor reducing the physiological phosphorylation of CK2 biomarkers and inducing cell death. Its binding mode to the ATP site was predicted to depend primarily on noncovalent interactions not comprising halogen bonds. We confirm this by two independent cocrystal structures which additionally show that FLC26 is selective for an open, protein kinase-untypical conformation of the hinge/helix αD region. The structures suggest how the bromo substituents, found previously in lead optimization studies, contribute to the inhibitory efficacy. In this context, one of the complex structures, obtained by crystallization with the kosmotropic salt NaCl, revealed an unconventional π-halogen bond between the 8-bromo substituent of FLC26 and an aromatic side chain which is absent under low-salt conditions. The kosmotropic salt sensitivity of π-halogen bonds is a novel feature which requires attention in structural comparisons and halogen-bond-based explanations.
- Published
- 2015
- Full Text
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6. Identification of apoptosis signal-regulating kinase 1 (ASK1) inhibitors among the derivatives of benzothiazol-2-yl-3-hydroxy-5-phenyl-1,5-dihydro-pyrrol-2-one.
- Author
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Starosyla SA, Volynets GP, Lukashov SS, Gorbatiuk OB, Golub AG, Bdzhola VG, and Yarmoluk SM
- Subjects
- Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Binding Sites, Enzyme Assays, High-Throughput Screening Assays, Humans, Hypoglycemic Agents chemical synthesis, Hypoglycemic Agents chemistry, Immunologic Factors chemical synthesis, Immunologic Factors chemistry, MAP Kinase Kinase Kinase 5 chemistry, Neuroprotective Agents chemical synthesis, Neuroprotective Agents chemistry, Protein Binding, Protein Kinase Inhibitors chemical synthesis, Pyrroles chemical synthesis, Recombinant Proteins, Small Molecule Libraries chemical synthesis, Structure-Activity Relationship, Thiazoles chemical synthesis, User-Computer Interface, MAP Kinase Kinase Kinase 5 antagonists & inhibitors, Protein Kinase Inhibitors chemistry, Pyrroles chemistry, Small Molecule Libraries chemistry, Thiazoles chemistry
- Abstract
Apoptosis signal-regulating kinase 1 (ASK1) plays important roles in the pathogenesis of type 1 and type 2 diabetes, autoimmune disorders, cancer and neurodegenerative diseases suggesting that small compounds inhibiting ASK1 could be used for the treatment of these pathologies. We have identified novel chemical class of ASK1 inhibitors, namely benzothiazol-2-yl-3-hydroxy-5-phenyl-1,5-dihydro-pyrrol-2-one, using molecular modeling techniques. It was found that the most active compound 1-(6-fluoro-benzothiazol-2-yl)-3-hydroxy-5-[3-(3-methyl-butoxy)-phenyl]-4-(2-methyl-2,3-dihydro-benzofuran-5-carbonyl)-1,5-dihydro-pyrrol-2-one (BPyO-34) inhibits ASK1 with IC50 of 0.52μM in vitro in kinase assay. The structure-activity relationships of 34 derivatives of benzothiazol-2-yl-3-hydroxy-5-phenyl-1,5-dihydro-pyrrol-2-one have been studied and binding mode of this chemical class has been proposed., (Copyright © 2015 Elsevier Ltd. All rights reserved.)
- Published
- 2015
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7. ASK1 pharmacophore model derived from diverse classes of inhibitors.
- Author
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Starosyla SA, Volynets GP, Bdzhola VG, Golub AG, Protopopov MV, and Yarmoluk SM
- Subjects
- Dose-Response Relationship, Drug, Drug Evaluation, Preclinical, Humans, MAP Kinase Kinase Kinase 5 metabolism, Models, Molecular, Molecular Conformation, Protein Kinase Inhibitors chemical synthesis, Protein Kinase Inhibitors chemistry, Structure-Activity Relationship, MAP Kinase Kinase Kinase 5 antagonists & inhibitors, Protein Kinase Inhibitors pharmacology
- Abstract
The three-dimensional pharmacophore model of apoptosis signal-regulating kinase 1 (ASK1) inhibitors has been developed with PharmaGist program. The positions of pharmacophore features in the model correspond to conformations of ASK1 highly active inhibitors in which they interact with ATP-binding site of ASK1. The generated pharmacophore model allows accurately predict active and inactive compounds and can be of great use for virtual screening aimed at discovering novel ASK1 inhibitors., (Copyright © 2014 Elsevier Ltd. All rights reserved.)
- Published
- 2014
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8. In vitro Activation of heme oxygenase-2 by menadione and its analogs.
- Author
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Vukomanovic D, Rahman MN, Bilokin Y, Golub AG, Brien JF, Szarek WA, Jia Z, and Nakatsu K
- Abstract
Background: Previously, we reported that menadione activated rat, native heme oxygenase-2 (HO-2) and human recombinant heme oxygenase-2 selectively; it did not activate spleen, microsomal heme oxygenase-1. The purpose of this study was to explore some structure-activity relationships of this activation and the idea that redox properties may be an important aspect of menadione efficacy., Methods: Heme oxygenase activity was determined in vitro using rat spleen and brain microsomes as the sources of heme oxygenase-1 and -2, respectively, as well as recombinant, human heme oxygenase-2., Results: Menadione analogs with bulky aliphatic groups at position-3, namely vitamins K1 and K2, were not able to activate HO-2. In contrast, several compounds with similar bulky but less lipophilic moieties at position-2 (and -3) were able to activate HO-2 many fold; these compounds included polar, rigid, furan-containing naphthoquinones, furan-benzoxazine naphthoquinones, 2-(aminophenylphenyl)-3-piperidin-1-yl naphthoquinones. To explore the idea that redox properties might be involved in menadione efficacy, we tested analogs such as 1,4-dimethoxy-2-methylnaphthalene, pentafluoromenadione, monohalogenated naphthoquinones, α-tetralone and 1,4-naphthoquinone. All of these compounds were inactive except for 1,4-naphthoquinone. Menadione activated full-length recombinant human heme oxygenase-2 (FL-hHO-2) as effectively as rat brain enzyme, but it did not activate rat spleen heme oxygenase., Conclusions: These observations are consistent with the idea that naphthoquinones such as menadione bind to a receptor in HO-2 and activate the enzyme through a mechanism that may involve redox properties.
- Published
- 2014
- Full Text
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9. Discovery and characterization of synthetic 4'-hydroxyflavones-New CK2 inhibitors from flavone family.
- Author
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Golub AG, Bdzhola VG, Ostrynska OV, Kyshenia IV, Sapelkin VM, Prykhod'ko AO, Kukharenko OP, and Yarmoluk SM
- Subjects
- Binding Sites, Casein Kinase II genetics, Casein Kinase II metabolism, Drug Design, Drug Evaluation, Preclinical, Flavones chemical synthesis, Flavones metabolism, Humans, Kinetics, Molecular Docking Simulation, Protein Binding, Protein Kinase Inhibitors chemical synthesis, Protein Kinase Inhibitors metabolism, Protein Structure, Tertiary, Recombinant Proteins biosynthesis, Recombinant Proteins chemistry, Recombinant Proteins genetics, Structure-Activity Relationship, Casein Kinase II antagonists & inhibitors, Flavones chemistry, Protein Kinase Inhibitors chemistry
- Abstract
Human protein kinase CK2 is one of the most intriguing enzymes, which functional role still remains unclear despite of decades of studying. At present there is abundant evidence pointing to the fact that inhibitors of CK2 could be used as pharmaceutical agents to treat cancer, viral infections and inflammatory diseases. Here we report novel synthetic flavone inhibitors, 4'-hydroxyflavones, possessing high activity towards CK2. These compounds were identified with receptor-based virtual screening and then chemically optimized on the base of rationale derived from biochemical screening and molecular modeling. It has been demonstrated that synthetic flavone derivatives are much more potent CK2 inhibitors than the natural ones, and we believe that their further examination will be helpful for studying biological role of CK2 as well as for development of new kinase-oriented drugs., (Copyright © 2013 Elsevier Ltd. All rights reserved.)
- Published
- 2013
- Full Text
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10. Identification of novel PARP-1 inhibitors by structure-based virtual screening.
- Author
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Hannigan K, Kulkarni SS, Bdzhola VG, Golub AG, Yarmoluk SM, and Talele TT
- Subjects
- Catalytic Domain, Drug Design, Enzyme Inhibitors pharmacology, Humans, Molecular Docking Simulation, Poly (ADP-Ribose) Polymerase-1, Poly(ADP-ribose) Polymerases chemistry, Poly(ADP-ribose) Polymerases metabolism, Pyrimidines pharmacology, Quinazolinones pharmacology, Structure-Activity Relationship, Enzyme Inhibitors chemistry, Poly(ADP-ribose) Polymerase Inhibitors, Pyrimidines chemistry, Quinazolinones chemistry
- Abstract
Poly(ADP-ribose)polymerase-1 (PARP-1) is an abundant and ubiquitous chromatin-bound nuclear protein. PARP-1, a DNA repair enzyme, has been in the limelight as a chemotherapeutic target. In this study, we demonstrated the successful use of structure-based virtual screening to identify inhibitors of PARP-1 from Otava databases comprised of nearly 260,000 compounds. Five novel inhibitors belonging to thienopyrimidinone, isoquinolinoquinazolinone, pyrroloquinazolinone, and cyclopentenothienopyrimidinone scaffolds revealed inhibitory potencies with IC50 values ranged from 9.57μM to 0.72μM. Structural features relevant to the activity of these novel compounds within the active site of PARP-1 are discussed in detail and will guide future SAR investigation on these scaffolds., (Copyright © 2013 Elsevier Ltd. All rights reserved.)
- Published
- 2013
- Full Text
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11. Rational design of apoptosis signal-regulating kinase 1 inhibitors: discovering novel structural scaffold.
- Author
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Volynets GP, Bdzhola VG, Golub AG, Synyugin AR, Chekanov MA, Kukharenko OP, and Yarmoluk SM
- Subjects
- Butyrates chemical synthesis, Butyrates chemistry, Caproates chemical synthesis, Caproates chemistry, Crystallography, X-Ray, Dose-Response Relationship, Drug, Humans, MAP Kinase Kinase Kinase 5 metabolism, Models, Molecular, Molecular Dynamics Simulation, Molecular Structure, Protein Kinase Inhibitors chemical synthesis, Structure-Activity Relationship, Thiazolidines chemical synthesis, Thiazolidines chemistry, Butyrates pharmacology, Caproates pharmacology, Drug Discovery, MAP Kinase Kinase Kinase 5 antagonists & inhibitors, Protein Kinase Inhibitors chemistry, Protein Kinase Inhibitors pharmacology, Thiazolidines pharmacology
- Abstract
Increased activity of apoptosis signal-regulating kinase 1 (ASK1) is associated with a number of human disorders and the inhibitors of ASK1 may become important compounds for pharmaceutical application. Here we report novel ASK1 inhibitor scaffold, namely 5-(5-Phenyl-furan-2-ylmethylene)-2-thioxo-thiazolidin-4-one, that has been identified using virtual screening and biochemical tests. A series of derivatives has been synthesized and evaluated in vitro towards human protein kinase ASK1. It was revealed that the most active compounds 4-((5Z)-5-{[5-(4-bromophenyl)-2-furyl]methylene}-4-oxo-2-thioxo-1,3-thiazolidin-3-yl)butanoic acid and 6-((5Z)-5-{[5-(4-bromophenyl)-2-furyl]methylene}-4-oxo-2-thioxo-1,3-thiazolidin-3-yl)hexanoic acid inhibit ASK1 with IC50 of 0.2 μM. Structure-activity relationships of 33 derivatives of 5-(5-Phenyl-furan-2-ylmethylene)-2-thioxo-thiazolidin-4-one have been studied and binding mode of this chemical class has been predicted., (Copyright © 2012 Elsevier Masson SAS. All rights reserved.)
- Published
- 2013
- Full Text
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12. Discovery of new scaffolds for rational design of HCV NS5B polymerase inhibitors.
- Author
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Golub AG, Gurukumar KR, Basu A, Bdzhola VG, Bilokin Y, Yarmoluk SM, Lee JC, Talele TT, Nichols DB, and Kaushik-Basu N
- Subjects
- Dose-Response Relationship, Drug, Enzyme Inhibitors chemistry, High-Throughput Screening Assays, Hydrazines chemistry, Models, Molecular, Molecular Structure, Quinazolinones chemistry, Structure-Activity Relationship, Viral Nonstructural Proteins genetics, Viral Nonstructural Proteins metabolism, Drug Discovery, Enzyme Inhibitors pharmacology, Hydrazines pharmacology, Quinazolinones pharmacology, Viral Nonstructural Proteins antagonists & inhibitors
- Abstract
Hepatitis C virus (HCV) NS5B polymerase is a key target for the development of anti-HCV drugs. Here we report on the identification of novel allosteric inhibitors of HCV NS5B through a combination of structure-based virtual screening and in vitro NS5B inhibition assays. One hundred and sixty thousand compounds from the Otava database were virtually screened against the thiazolone inhibitor binding site on NS5B (thumb pocket-2, TP-2), resulting in a sequential down-sizing of the library by 2.7 orders of magnitude to yield 59 NS5B non-nucleoside inhibitor (NNI) candidates. In vitro evaluation of the NS5B inhibitory activity of the 59 selected compounds resulted in a 14% hit rate, yielding 8 novel structural scaffolds. Of these, compound 1 bearing a 4-hydrazinoquinazoline scaffold was the most active (IC(50) = 16.0 μM). The binding site of all 8 NNIs was mapped to TP-2 of NS5B as inferred by a decrease in their inhibition potency against the M423T NS5B mutant, employed as a screen for TP-2 site binders. At 100 μM concentration, none of the eight compounds exhibited any cytotoxicity, and all except compound 8 exhibited between 40 and 60% inhibition of intracellular NS5B polymerase activity in BHK-NS5B-FRLuc reporter cells. These inhibitor scaffolds will form the basis for future optimization and development of more potent NS5B inhibitors., (Copyright © 2012 Elsevier Masson SAS. All rights reserved.)
- Published
- 2012
- Full Text
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13. Structure-based discovery of novel flavonol inhibitors of human protein kinase CK2.
- Author
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Golub AG, Bdzhola VG, Kyshenia YV, Sapelkin VM, Prykhod'ko AO, Kukharenko OP, Ostrynska OV, and Yarmoluk SM
- Subjects
- Casein Kinase II metabolism, Catalytic Domain, Flavonols chemistry, Humans, Hydrogen Bonding drug effects, Kinetics, Molecular Dynamics Simulation, Protein Kinase Inhibitors chemistry, Structure-Activity Relationship, Substrate Specificity drug effects, Thermodynamics, Casein Kinase II antagonists & inhibitors, Drug Discovery, Flavonols pharmacology, Protein Kinase Inhibitors pharmacology
- Abstract
Serine/threonine protein kinase CK2 controls vast variety of fundamental processes in cell life; however, despite long period of study, its functional role is not completely determined. CK2 has a significant pathogenic potential and its activity is strictly associated with the development of various kinds of disorders. There are a growing number of facts that inhibitors of CK2 could be used as pharmaceutical agents for the cancer treatment, viral infections, and inflammatory diseases. In this article, we report structural and biological data on the novel synthetic flavonol derivatives, 3-hydroxy-4'-carboxyflavones, possessing a high inhibitory activity toward CK2. With the aid of combinatorial organic synthesis, molecular modeling techniques and biochemical in vitro tests, we studied the structure-activity relationships of flavonol derivatives and developed binding model describing their key intermolecular interactions with the CK2 ATP-binding site. Obtained data show that the synthetic 3-hydroxy-4'-carboxyflavones possess the highest activity among flavonol inhibitors of CK2 known till date.
- Published
- 2011
- Full Text
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14. Identification of 3H-naphtho[1,2,3-de]quinoline-2,7-diones as inhibitors of apoptosis signal-regulating kinase 1 (ASK1).
- Author
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Volynets GP, Chekanov MO, Synyugin AR, Golub AG, Kukharenko OP, Bdzhola VG, and Yarmoluk SM
- Subjects
- Animals, Aporphines chemistry, Magnetic Resonance Spectroscopy, Mice, Models, Molecular, Molecular Dynamics Simulation, Quinolines chemistry, Quinolones chemistry, Aporphines pharmacology, MAP Kinase Kinase Kinase 5 antagonists & inhibitors, Protein Kinase Inhibitors pharmacology, Quinolines pharmacology, Quinolones pharmacology
- Abstract
Apoptosis signal-regulating kinase 1 (ASK1) has recently emerged as an attractive therapeutic target for the treatment of cardiac and neurodegenerative disorders. The selective inhibitors of ASK1 may become important compounds for the development of clinical agents. We have identified the ASK1 inhibitor among 3H-naphtho[1,2,3-de]quinoline-2,7-diones using receptor-based virtual screening. In vitro kinase assay revealed that ethyl 2,7-dioxo-2,7-dihydro-3H-naphtho[1,2,3-de]quinoline-1-carboxylate (NQDI-1) inhibited ASK1 with a K(i) of 500 nM. The competitive character of inhibition is demonstrated in Lineweaver-Burk plots. In our preliminary selectivity study this compound exhibited strong specific inhibitory activity toward ASK1.
- Published
- 2011
- Full Text
- View/download PDF
15. Synthesis and biological evaluation of substituted (thieno[2,3-d]pyrimidin-4-ylthio)carboxylic acids as inhibitors of human protein kinase CK2.
- Author
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Golub AG, Bdzhola VG, Briukhovetska NV, Balanda AO, Kukharenko OP, Kotey IM, Ostrynska OV, and Yarmoluk SM
- Subjects
- Carboxylic Acids chemical synthesis, Carboxylic Acids chemistry, Carboxylic Acids pharmacology, Humans, Models, Molecular, Protein Kinase Inhibitors chemical synthesis, Pyrimidines chemical synthesis, Structure-Activity Relationship, Casein Kinase II antagonists & inhibitors, Casein Kinase II metabolism, Protein Kinase Inhibitors chemistry, Protein Kinase Inhibitors pharmacology, Pyrimidines chemistry, Pyrimidines pharmacology
- Abstract
A novel series of substituted (thieno[2,3-d]pyrimidin-4-ylthio)carboxylic acids has been synthesized and tested in vitro towards human protein kinase CK2. It was revealed that the most active compounds inhibiting CK2 are 3-{[5-(4-methylphenyl)thieno[2,3-d]pyrimidin-4-yl]thio}propanoic acid and 3-{[5-(4-ethoxyphenyl)thieno[2,3-d]pyrimidin-4-yl]thio}propanoic acid (IC(50) values are 0.1 μM and 0.125 μM, respectively). Structure-activity relationships of 28 tested thienopyrimidine derivatives have been studied and binding mode of this chemical class has been predicted. Evaluation of the inhibitors on seven protein kinases revealed considerable selectivity towards CK2., (Copyright © 2011 Elsevier Masson SAS. All rights reserved.)
- Published
- 2011
- Full Text
- View/download PDF
16. Evaluation of 3-carboxy-4(1H)-quinolones as inhibitors of human protein kinase CK2.
- Author
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Golub AG, Yakovenko OY, Bdzhola VG, Sapelkin VM, Zien P, and Yarmoluk SM
- Subjects
- Adenosine Triphosphate metabolism, Computer Simulation, Drug Evaluation, Preclinical, Hydrogen Bonding, Indicators and Reagents, Ligands, Models, Molecular, Receptors, Drug chemistry, Receptors, Drug genetics, Recombinant Proteins, Software, Structure-Activity Relationship, Substrate Specificity, Casein Kinase II antagonists & inhibitors, Enzyme Inhibitors chemical synthesis, Enzyme Inhibitors pharmacology, Quinolones chemical synthesis, Quinolones pharmacology
- Abstract
Due to the emerging role of protein kinase CK2 as a molecule that participates not only in the development of some cancers but also in viral infections and inflammatory failures, small organic inhibitors of CK2, besides application in scientific research, may have therapeutic significance. In this paper, we present a new class of CK2 inhibitors-3-carboxy-4(1H)-quinolones. This class of inhibitors has been selected via receptor-based virtual screening of the Otava compound library. It was revealed that the most active compounds, 5,6,8-trichloro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (7) (IC(50) = 0.3 microM) and 4-oxo-1,4-dihydrobenzo[h]quinoline-3-carboxylic acid (9) (IC(50) = 1 microM), are ATP competitive (K(i) values are 0.06 and 0.28 microM, respectively). Evaluation of the inhibitors on seven protein kinases shows considerable selectivity toward CK2. According to theoretical calculations and experimental data, a structural model describing the key features of 3-carboxy-4(1H)-quinolones responsible for tight binding to CK2 active site has been developed.
- Published
- 2006
- Full Text
- View/download PDF
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