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{vyhlidalova_gut_2020,

title = {Gut Microbial Catabolites of Tryptophan Are Ligands and Agonists of the Aryl Hydrocarbon Receptor: A Detailed Characterization.},

author = {Barbora Vyhlídalová and Kristýna Krasulová and Petra Pečinková and Adéla Marcalíková and Radim Vrzal and Lenka Zemánková and Jan Vančo and Zdeněk Trávníček and Jan Vondráček and Martina Karasová and Sridhar Mani and Zdeněk Dvořák},

doi = {10.3390/ijms21072614},

issn = {1422-0067},

year  = {2020},

date = {2020-04-01},

journal = {International journal of molecular sciences},

volume = {21},

number = {7},

abstract = {We examined the effects of gut microbial catabolites of tryptophan on the aryl hydrocarbon receptor (AhR). Using a reporter gene assay, we show that all studied catabolites are low-potency agonists of human AhR. The efficacy of catabolites differed substantially, comprising agonists with no or low (i3-propionate, i3-acetate, i3-lactate, i3-aldehyde), medium (i3-ethanol, i3-acrylate, skatole, tryptamine), and high (indole, i3-acetamide, i3-pyruvate) efficacies. We displayed ligand-selective antagonist activities by i3-pyruvate, i3-aldehyde, indole, skatole, and tryptamine. Ligand binding assay identified low affinity (skatole, i3-pyruvate, and i3-acetamide) and very low affinity (i3-acrylate, i3-ethanol, indole) ligands of the murine AhR. Indole, skatole, tryptamine, i3-pyruvate, i3-acrylate, and i3-acetamide induced CYP1A1 mRNA in intestinal LS180 and HT-29 cells, but not in the AhR-knockout HT-29 variant. We observed a similar CYP1A1 induction pattern in primary human hepatocytes. The most AhR-active catabolites (indole, skatole, tryptamine, i3-pyruvate, i3-acrylate, i3-acetamide) elicited nuclear translocation of the AhR, followed by a formation of AhR-ARNT heterodimer and enhanced binding of the AhR to the CYP1A1 gene promoter. Collectively, we comprehensively characterized the interactions of gut microbial tryptophan catabolites with the AhR, which may expand the current understanding of their potential roles in intestinal health and disease.},

note = {Place: Switzerland},

keywords = {*Gastrointestinal Microbiome/drug effects, Animals, Aryl hydrocarbon receptor, Aryl Hydrocarbon/*agonists/*metabolism, Basic Helix-Loop-Helix Transcription Factors/*agonists/*metabolism, Cell Line, Cytochrome P-450 CYP1A1/genetics, Gene Expression, Genes, Genetic, Humans, Indoles, Ligands, Metabolic Networks and Pathways, Mice, Microbiome, Promoter Regions, Protein Binding, Protein Multimerization, Receptors, Reporter, tryptophan, Tryptophan/*metabolism, Tumor},

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}

}