Latest Publications

@article{nemec_highly_2021,

title = {Highly selective inhibitors of protein kinases CLK and HIPK with the furo[3,2-b]pyridine core.},

author = {Václav Němec and Lukáš Maier and Benedict-Tilman Berger and Apirat Chaikuad and Stanislav Drápela and Karel Souček and Stefan Knapp and Kamil Paruch},

doi = {10.1016/j.ejmech.2021.113299},

issn = {1768-3254 0223-5234},

year  = {2021},

date = {2021-04-01},

journal = {European journal of medicinal chemistry},

volume = {215},

pages = {113299},

abstract = {The furo [3,2-b]pyridine motif represents a relatively underexplored central pharmacophore in the area of kinase inhibitors. Herein, we report flexible synthesis of 3,5-disubstituted furo [3,2-b]pyridines that relies on chemoselective couplings of newly prepared 5-chloro-3-iodofuro [3,2-b]pyridine. This methodology allowed efficient second-generation synthesis of the state-of-the-art chemical biology probe for CLK1/2/4 MU1210, and identification of the highly selective inhibitors of HIPKs MU135 and MU1787 which are presented and characterized in this study, including the X-ray crystal structure of MU135 in HIPK2. chemical biology probe.},

note = {Place: France},

keywords = {2-b]pyridine, Animals, Carrier Proteins/*antagonists & inhibitors/metabolism, CLK, Crystallography, Furans/chemical synthesis/metabolism/*pharmacology, Furo[3, HIPK, Humans, Inhibitor, Kinase, MCF-7 Cells, Mice, Molecular Structure, MU1210, MU135, MU1787, Protein Binding, Protein Kinase Inhibitors/chemical synthesis/metabolism/*pharmacology, Protein Serine-Threonine Kinases/*antagonists & inhibitors/metabolism, Pyridines/chemical synthesis/metabolism/*pharmacology, Structure-Activity Relationship, X-Ray},

pubstate = {published},

tppubtype = {article}

}

@article{kauerova_ring-substituted_2020,

title = {Ring-Substituted 1-Hydroxynaphthalene-2-Carboxanilides Inhibit Proliferation and Trigger Mitochondria-Mediated Apoptosis.},

author = {Tereza Kauerová and Tomáš Goněc and Josef Jampílek and Susanne Hafner and Ann-Kathrin Gaiser and Tatiana Syrovets and Radek Fedr and Karel Souček and Peter Kollar},

doi = {10.3390/ijms21103416},

issn = {1422-0067},

year  = {2020},

date = {2020-05-01},

journal = {International journal of molecular sciences},

volume = {21},

number = {10},

abstract = {Ring-substituted 1-hydroxynaphthalene-2-carboxanilides were previously investigated for their antimycobacterial properties. In our study, we have shown their antiproliferative and cell death-inducing effects in cancer cell lines. Cell proliferation and viability were assessed by WST-1 assay and a dye exclusion test, respectively. Cell cycle distribution, phosphatidylserine externalization, levels of reactive oxygen or nitrogen species (RONS), mitochondrial membrane depolarization, and release of cytochrome c were estimated by flow cytometry. Levels of regulatory proteins were determined by Western blotting. Our data suggest that the ability to inhibit the proliferation of THP-1 or MCF-7 cells might be referred to meta- or para-substituted derivatives with electron-withdrawing groups -F, -Br, or -CF(3) at anilide moiety. This effect was accompanied by accumulation of cells in G1 phase. Compound 10 also induced apoptosis in THP-1 cells in association with a loss of mitochondrial membrane potential and production of mitochondrial superoxide. Our study provides a new insight into the action of salicylanilide derivatives, hydroxynaphthalene carboxamides, in cancer cells. Thus, their structure merits further investigation as a model moiety of new small-molecule compounds with potential anticancer properties.},

note = {Place: Switzerland},

keywords = {Anilides/chemistry/*pharmacology, Antineoplastic Agents/chemistry/pharmacology, antiproliferative effect, Apoptosis, Apoptosis/*drug effects, Cell Cycle, Cell Cycle/drug effects, Cell Proliferation/*drug effects, Cell Survival/drug effects, Humans, hydroxynaphthalene carboxamides, MCF-7 Cells, Membrane Potential, Mitochondria/*drug effects/metabolism, Mitochondrial/drug effects, Molecular Structure, Naphthols/*chemistry, Reactive Oxygen Species/metabolism, salicylanilides, Salicylanilides/chemistry/pharmacology, Structure-Activity Relationship, Superoxides/metabolism, THP-1 Cells},

pubstate = {published},

tppubtype = {article}

}

@article{nemec_furo32-bpyridine_2019,

title = {Furo[3,2-b]pyridine: A Privileged Scaffold for Highly Selective Kinase Inhibitors and Effective Modulators of the Hedgehog Pathway.},

author = {Václav Němec and Michaela Hylsová and Lukáš Maier and Jana Flegel and Sonja Sievers and Slava Ziegler and Martin Schröder and Benedict-Tilman Berger and Apirat Chaikuad and Barbora Valčíková and Stjepan Uldrijan and Stanislav Drápela and Karel Souček and Herbert Waldmann and Stefan Knapp and Kamil Paruch},

doi = {10.1002/anie.201810312},

issn = {1521-3773 1433-7851},

year  = {2019},

date = {2019-01-01},

journal = {Angewandte Chemie (International ed. in English)},

volume = {58},

number = {4},

pages = {1062–1066},

abstract = {Reported is the identification of the furo[3,2-b]pyridine core as a novel scaffold for potent and highly selective inhibitors of cdc-like kinases (CLKs) and efficient modulators of the Hedgehog signaling pathway. Initially, a diverse target compound set was prepared by synthetic sequences based on chemoselective metal-mediated couplings, including assembly of the furo[3,2-b]pyridine scaffold by copper-mediated oxidative cyclization. Optimization of the subseries containing 3,5-disubstituted furo[3,2-b]pyridines afforded potent, cell-active, and highly selective inhibitors of CLKs. Profiling of the kinase-inactive subset of 3,5,7-trisubstituted furo[3,2-b]pyridines revealed sub-micromolar modulators of the Hedgehog pathway.},

note = {Place: Germany},

keywords = {Binding Sites, biological activity, Cell Survival/drug effects, chemical probes, Furans/*chemistry, Hedgehog Proteins/*chemistry, heterocycles, Humans, inhibitors, Inhibitory Concentration 50, kinases, MCF-7 Cells, Molecular Structure, Protein Binding, Protein Kinase Inhibitors/*chemical synthesis/chemistry/pharmacology, Pyridines/*chemistry, Small Molecule Libraries/*chemical synthesis/chemistry/pharmacology},

pubstate = {published},

tppubtype = {article}

}

@article{hyzdalova_aryl_2018,

title = {Aryl Hydrocarbon Receptor-Dependent Metabolism Plays a Significant Role in Estrogen-Like Effects of Polycyclic Aromatic Hydrocarbons on Cell Proliferation.},

author = {Martina Hýžd'alová and Jakub Pivnicka and Ondrej Zapletal and Gerardo Vázquez-Gómez and Jason Matthews and Jirí Neca and Katerina Pencíková and Miroslav Machala and Jan Vondrácek},

doi = {10.1093/toxsci/kfy153},

issn = {1096-0929 1096-6080},

year  = {2018},

date = {2018-10-01},

journal = {Toxicological sciences : an official journal of the Society of Toxicology},

volume = {165},

number = {2},

pages = {447–461},

abstract = {Polycyclic aromatic hydrocarbons (PAHs) are widespread environmental contaminants that interact in a complex manner with both the aryl hydrocarbon receptor (AhR) and estrogen receptors (ER). Their potential endocrine-disrupting activities may depend on both inhibitory AhR-ER cross-talk and on AhR-dependent metabolic production of estrogenic PAH metabolites. Here, we analyzed the impact of AhR on estrogen-like effects of PAHs, such as benzo[a]pyrene (BaP), in particular, on control of cell cycle progression/cell proliferation. Using AhR knockout variant of estrogen-sensitive human breast cancer MCF-7 cells (MCF-7 AhRKO cells), we observed that the AhR-dependent control of cytochrome P450 family 1 (CYP1) expression played a major role in formation of estrogenic BaP metabolites, most notably 3-OH-BaP, which contributed to the ER-dependent induction of cell cycle progression/cell proliferation. Both BaP metabolism and the BaP-induced S-phase transition/cell proliferation were inhibited in MCF-7 AhRKO cells, whereas these cells remained sensitive towards both endogenous estrogen 17β-estradiol or hydroxylated BaP metabolites. BaP was found to increase the activity of ER-dependent luciferase reporter gene in wild-type MCF-7 cells; however, unlike its hydroxylated metabolite, BaP failed to stimulate luciferase activity in MCF-7 AhRKO cells. Similarly, estrogen-like effects of other known estrogenic PAHs, such as benz[a]anthracene or 3-methylcholanthrene, were diminished in MCF-7 AhRKO cells. Ectopic expression of human CYP1A1 and CYP1B1 enzymes partly restored both BaP metabolism and its effects on cell proliferation. Taken together, our data suggest that the AhR-dependent metabolism of PAHs contributes significantly to the impact of PAHs on cell proliferation in estrogen-sensitive cells.},

note = {Place: United States},

keywords = {Aryl Hydrocarbon/genetics/*metabolism, Cell Culture Techniques, Cell Cycle/drug effects/genetics, Cell Proliferation/*drug effects/genetics, Cytochrome P-450 CYP1A1/genetics/metabolism, Cytochrome P-450 CYP1B1/genetics/metabolism, Endocrine Disruptors/metabolism/*toxicity, Estrogen/genetics/metabolism, Gene Expression/drug effects, Gene Knockdown Techniques, Genes, Genetic Vectors, Humans, MCF-7 Cells, Plasmids, Polycyclic Aromatic Hydrocarbons/metabolism/*toxicity, Receptors, Reporter, Transfection},

pubstate = {published},

tppubtype = {article}

}