Latest Publications

@article{nemec_discovery_2024,

title = {Discovery of Two Highly Selective Structurally Orthogonal Chemical Probes for Activin Receptor-like Kinases 1 and 2.},

author = {Václav Němec and Marek Remeš and Petr Beňovský and Michael C. Böck and Eliška Šranková and Jong Fu Wong and Julien Cros and Eleanor Williams and Lap Hang Tse and David Smil and Deeba Ensan and Methvin B. Isaac and Rima Al-Awar and Regina Gomolková and Vlad-Constantin Ursachi and Bohumil Fafílek and Zuzana Kahounová and Ráchel Víchová and Ondřej Vacek and Benedict-Tilman Berger and Carrow I. Wells and Cesear R. Corona and James D. Vasta and Matthew B. Robers and Pavel Krejci and Karel Souček and Alex N. Bullock and Stefan Knapp and Kamil Paruch},

doi = {10.1021/acs.jmedchem.4c00629},

issn = {1520-4804 0022-2623},

year  = {2024},

date = {2024-08-01},

journal = {Journal of medicinal chemistry},

volume = {67},

number = {15},

pages = {12632–12659},

abstract = {Activin receptor-like kinases 1-7 (ALK1-7) regulate a complex network of SMAD-independent as well as SMAD-dependent signaling pathways. One of the widely used inhibitors for functional investigations of these processes, in particular for bone morphogenetic protein (BMP) signaling, is LDN-193189. However, LDN-193189 has insufficient kinome-wide selectivity complicating its use in cellular target validation assays. Herein, we report the identification and comprehensive characterization of two chemically distinct highly selective inhibitors of ALK1 and ALK2, M4K2234 and MU1700, along with their negative controls. We show that both MU1700 and M4K2234 efficiently block the BMP pathway via selective in cellulo inhibition of ALK1/2 kinases and exhibit favorable in vivo profiles in mice. MU1700 is highly brain penetrant and shows remarkably high accumulation in the brain. These high-quality orthogonal chemical probes offer the selectivity required to become widely used tools for in vitro and in vivo investigation of BMP signaling.},

note = {Place: United States},

keywords = {*Activin Receptors, Activin Receptors, Animals, Bone Morphogenetic Proteins/metabolism, Drug Discovery, Humans, Mice, Molecular Probes/chemistry, Protein Kinase Inhibitors/pharmacology/chemistry, Pyrazoles/chemistry/pharmacology/chemical synthesis, Signal Transduction/drug effects, Structure-Activity Relationship, Type I/antagonists & inhibitors/metabolism, Type II/metabolism/antagonists & inhibitors},

pubstate = {published},

tppubtype = {article}

}

@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{forejtnikova_chemoprotective_2005,

title = {Chemoprotective and toxic potentials of synthetic and natural chalcones and dihydrochalcones in vitro.},

author = {Hana Forejtníková and Kamila Lunerová and Renata Kubínová and Dagmar Jankovská and Radek Marek and Radovan Kares and Václav Suchý and Jan Vondrácek and Miroslav Machala},

doi = {10.1016/j.tox.2004.11.011},

issn = {0300-483X},

year  = {2005},

date = {2005-03-01},

journal = {Toxicology},

volume = {208},

number = {1},

pages = {81–93},

abstract = {Cytochrome P4501A activity, oxidative stress and inhibition of gap junctional intercellular communication (GJIC) are involved in metabolic activation of promutagens and tumor-promoting activity of various xenobiotics, and their prevention is considered to be an important characteristic of chemoprotective compounds. In this study, a series of 31 chalcones and their corresponding dihydroderivatives, substituted in 2,2'-, 3,3'-, 4- or 4'-position by hydroxyl or methoxy group, were tested for their ability to inhibit Fe(II)/NADPH-enhanced lipid peroxidation and cytochrome P4501A-dependent 7-cethoxyresorufin-O-deethylase (EROD) activity in rat hepatic microsomes. Effects of the compounds on GJIC were determined in rat liver epithelial WB-F344 cells. Most of the chalcones and dihydrochalcones inhibited EROD activity in a dose-dependent manner at the range 0.25-25 microM, which was comparable to model flavonoid inhibitors alpha-naphthoflavone and quercetin. The chalcones exhibited higher inhibition activity than the corresponding dihydroderivatives. Mono and dihydroxylated chalcones, and dihydrochalcones showed none or only a weak antioxidant activity; trihydroxyderivatives inhibited in vitro lipid peroxidation significantly only at 50 microM concentration. Potential adverse effects, namely inhibition of GJIC and/or cytotoxicity were detected after treatment of WB-F344 cells with a number of chalcone and dihydrochalcone derivatives, suggesting that they should be excluded from additional screening as chemoprotective compounds. Chalcones and dihydrochalcones substituted at 4- and/or 4'-position, which elicited no inhibition of GJIC, were further tested for the potential enhancing effects on GJIC. The present data seem to suggest that 4-hydroxy, 2',4'-dihydroxy-3-methoxy, 2,4,4'-trihydroxy, and 2',4,4'-trihydroxychalcone, 2',4-dihydroxy and 2'-hydroxy-3,4-dimethoxydihydrochalcone might be promising chemoprotective compounds against CYP1A activity, and partly also against oxidative damage without inducing adverse effects, such as GJIC inhibition. In general, determination of potencies of tested compounds to inhibit GJIC should be involved in any set of methods for the in vitro screening of chemoprotective characteristics of potential drugs, in order to reveal their potential adverse effects associated with tumor promotion.},

note = {Place: Ireland},

keywords = {Animals, Carcinogens/metabolism/*toxicity, Cell Communication/drug effects/physiology, Cell Line, Chalcones/*pharmacology/*toxicity, Cytochrome P-450 Enzyme Inhibitors, Cytochrome P-450 Enzyme System/*metabolism, Dose-Response Relationship, Drug, Epithelial Cells/drug effects/metabolism, Gap Junctions/drug effects/metabolism/physiology, In Vitro Techniques, Lipid Peroxidation/drug effects, Liver/drug effects/enzymology, Liver/drug effects/ultrastructure, Male, Microsomes, Rats, Structure-Activity Relationship, Wistar},

pubstate = {published},

tppubtype = {article}

}