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  1. Article ; Online: Direct and selective pharmacological disruption of the YAP-TEAD interface by IAG933 inhibits Hippo-dependent and RAS-MAPK-altered cancers.

    Chapeau, Emilie A / Sansregret, Laurent / Galli, Giorgio G / Chène, Patrick / Wartmann, Markus / Mourikis, Thanos P / Jaaks, Patricia / Baltschukat, Sabrina / Barbosa, Ines A M / Bauer, Daniel / Brachmann, Saskia M / Delaunay, Clara / Estadieu, Claire / Faris, Jason E / Furet, Pascal / Harlfinger, Stefanie / Hueber, Andreas / Jiménez Núñez, Eloísa / Kodack, David P /
    Mandon, Emeline / Martin, Typhaine / Mesrouze, Yannick / Romanet, Vincent / Scheufler, Clemens / Sellner, Holger / Stamm, Christelle / Sterker, Dario / Tordella, Luca / Hofmann, Francesco / Soldermann, Nicolas / Schmelzle, Tobias

    Nature cancer

    2024  

    Abstract: The YAP-TEAD protein-protein interaction mediates YAP oncogenic functions downstream of the Hippo pathway. To date, available YAP-TEAD pharmacologic agents bind into the lipid pocket of TEAD, targeting the interaction indirectly via allosteric changes. ... ...

    Abstract The YAP-TEAD protein-protein interaction mediates YAP oncogenic functions downstream of the Hippo pathway. To date, available YAP-TEAD pharmacologic agents bind into the lipid pocket of TEAD, targeting the interaction indirectly via allosteric changes. However, the consequences of a direct pharmacological disruption of the interface between YAP and TEADs remain largely unexplored. Here, we present IAG933 and its analogs as potent first-in-class and selective disruptors of the YAP-TEAD protein-protein interaction with suitable properties to enter clinical trials. Pharmacologic abrogation of the interaction with all four TEAD paralogs resulted in YAP eviction from chromatin and reduced Hippo-mediated transcription and induction of cell death. In vivo, deep tumor regression was observed in Hippo-driven mesothelioma xenografts at tolerated doses in animal models as well as in Hippo-altered cancer models outside mesothelioma. Importantly this also extended to larger tumor indications, such as lung, pancreatic and colorectal cancer, in combination with RTK, KRAS-mutant selective and MAPK inhibitors, leading to more efficacious and durable responses. Clinical evaluation of IAG933 is underway.
    Language English
    Publishing date 2024-04-02
    Publishing country England
    Document type Journal Article
    ISSN 2662-1347
    ISSN (online) 2662-1347
    DOI 10.1038/s43018-024-00754-9
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: Further investigations into the genotoxicity of 2,6-xylidine and one of its key metabolites

    Kirkland, David / Ballantyne, Mark / Harlfinger, Stefanie / Will, Olaf / Jahnel, Ulrich / Kraus, Alexander / Dorp, Corinne van

    Regulatory toxicology and pharmacology. 2012 Feb., v. 62, no. 1

    2012  

    Abstract: The metabolite of several amide anaesthetics, 2,6-xylidine, is a possible human (Group 2B) carcinogen and induced nasal tumours in rats after dietary administration. However, published papers on the genotoxicity of 2,6-xylidine in vitro have given ... ...

    Abstract The metabolite of several amide anaesthetics, 2,6-xylidine, is a possible human (Group 2B) carcinogen and induced nasal tumours in rats after dietary administration. However, published papers on the genotoxicity of 2,6-xylidine in vitro have given inconsistent results. It has been proposed that the genotoxicity of 2,6-xylidine is dependent on its metabolism to a key metabolite dimethylphenyl N-hydroxylamine (DMHA), which would then be further converted to form a reactive nitrenium ion by phase 2 (mainly acetylation) metabolism. In order to study whether the inconsistent results could be explained by different systems having different potential for DMHA to be formed and to induce genotoxicity in vitro, we have tested 2,6-xylidine in conventional Ames bacteria, and strains engineered to overexpress acetyltransferase, in the presence of different concentrations of induced rat liver and human liver S9. All tests gave consistently negative results. The formation of DMHA by induced rat liver S9 and human S9 was clearly shown to occur, and to be concentration- and time-dependent. The potential inhibitory effects of the solvent DMSO were also studied, but it was clearly not responsible for the negative results with 2,6-xylidine. Thus, whatever is the mode of action of 2,6-xylidine carcinogenicity in rodents, it has proven impossible to detect mutagenic effects in Ames tests with numerous variations of metabolic conditions, or even using acetyltransferase overexpressing strains of bacteria.
    Keywords acetylation ; anesthetics ; bacteria ; carcinogenicity ; carcinogens ; dimethyl sulfoxide ; genotoxicity ; humans ; liver ; mechanism of action ; metabolism ; metabolites ; mutagenicity ; neoplasms ; nose ; rats ; solvents
    Language English
    Dates of publication 2012-02
    Size p. 151-159.
    Publishing place Elsevier Inc.
    Document type Article
    ZDB-ID 604672-1
    ISSN 0273-2300
    ISSN 0273-2300
    DOI 10.1016/j.yrtph.2011.08.010
    Database NAL-Catalogue (AGRICOLA)

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    Zs.A 1711: Show issues Location:
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  3. Article: Quantification of mephenytoin and its metabolites 4'-hydroxymephenytoin and nirvanol in human urine using a simple sample processing method.

    Klaassen, Tobias / Kasel, Dirk / Harlfinger, Stefanie / Fuhr, Uwe

    Rapid communications in mass spectrometry : RCM

    2004  Volume 18, Issue 15, Page(s) 1675–1680

    Abstract: A reliable and easy to use liquid chromatography/tandem mass spectrometry (LC/MS/MS) method without the use of sample extraction was developed for the simultaneous quantification of urinary concentrations of mephenytoin, a standard phenotyping substrate ... ...

    Abstract A reliable and easy to use liquid chromatography/tandem mass spectrometry (LC/MS/MS) method without the use of sample extraction was developed for the simultaneous quantification of urinary concentrations of mephenytoin, a standard phenotyping substrate for the cytochrome P450 enzyme CYP2C19, and its phase I metabolites 4'-hydroxymephenytoin and nirvanol. Fifty microL of urine were diluted with a buffered beta-glucuronidase solution and incubated at 37 degrees C for 6 h followed by addition of methanol, containing the internal standard 4'-methoxymephenytoin. The chromatographic separation was achieved using a 100 x 3 mm, 5 micro Thermo Electron Aquasil C18 column with a gradient flow, increasing the organic fraction (acetonitrile/methanol 50:50) of the mobile phase from 10 to 90%. Quantification by triple-stage mass spectrometry (TSQ Quantum, Thermo Electron) was accomplished by negative electrospray ionization in the selected reaction monitoring mode. Linearity was observed for all substances in the concentration range 15-10 000 ng/mL. The lower limit of quantification (LLOQ) was 20 ng/mL for 4'-hydroxymephenytoin and 30 ng/mL for nirvanol and mephenytoin, respectively. Intra- and inter-day inaccuracy did not exceed 9.5% for all substances from LLOQ to 10 000 ng/mL. Intra- and inter-day precision were in the range of 0.8-10.5%. The method was validated according to international ICH and FDA guidelines and successfully applied for phenotyping of Caucasian male volunteers who received an oral dose of 50 mg mephenytoin.
    MeSH term(s) Aryl Hydrocarbon Hydroxylases/genetics ; Calibration ; Chromatography, Liquid ; Cytochrome P-450 CYP2C19 ; Humans ; Male ; Mass Spectrometry ; Mephenytoin/analogs & derivatives ; Mephenytoin/metabolism ; Mephenytoin/urine ; Mixed Function Oxygenases/genetics ; Molecular Structure ; Reference Standards ; Reproducibility of Results ; Sensitivity and Specificity
    Chemical Substances ethylphenylhydantoin (23SM1FA1AK) ; 4-hydroxymephenytoin (61837-65-8) ; Mixed Function Oxygenases (EC 1.-) ; Aryl Hydrocarbon Hydroxylases (EC 1.14.14.1) ; CYP2C19 protein, human (EC 1.14.14.1) ; Cytochrome P-450 CYP2C19 (EC 1.14.14.1) ; Mephenytoin (R420KW629U)
    Language English
    Publishing date 2004
    Publishing country England
    Document type Journal Article
    ZDB-ID 58731-x
    ISSN 1097-0231 ; 0951-4198
    ISSN (online) 1097-0231
    ISSN 0951-4198
    DOI 10.1002/rcm.1539
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 3461: Show issues Location:
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  4. Article ; Online: Further investigations into the genotoxicity of 2,6-xylidine and one of its key metabolites.

    Kirkland, David / Ballantyne, Mark / Harlfinger, Stefanie / Will, Olaf / Jahnel, Ulrich / Kraus, Alexander / Dorp, Corinne van

    Regulatory toxicology and pharmacology : RTP

    2012  Volume 62, Issue 1, Page(s) 151–159

    Abstract: The metabolite of several amide anaesthetics, 2,6-xylidine, is a possible human (Group 2B) carcinogen and induced nasal tumours in rats after dietary administration. However, published papers on the genotoxicity of 2,6-xylidine in vitro have given ... ...

    Abstract The metabolite of several amide anaesthetics, 2,6-xylidine, is a possible human (Group 2B) carcinogen and induced nasal tumours in rats after dietary administration. However, published papers on the genotoxicity of 2,6-xylidine in vitro have given inconsistent results. It has been proposed that the genotoxicity of 2,6-xylidine is dependent on its metabolism to a key metabolite dimethylphenyl N-hydroxylamine (DMHA), which would then be further converted to form a reactive nitrenium ion by phase 2 (mainly acetylation) metabolism. In order to study whether the inconsistent results could be explained by different systems having different potential for DMHA to be formed and to induce genotoxicity in vitro, we have tested 2,6-xylidine in conventional Ames bacteria, and strains engineered to overexpress acetyltransferase, in the presence of different concentrations of induced rat liver and human liver S9. All tests gave consistently negative results. The formation of DMHA by induced rat liver S9 and human S9 was clearly shown to occur, and to be concentration- and time-dependent. The potential inhibitory effects of the solvent DMSO were also studied, but it was clearly not responsible for the negative results with 2,6-xylidine. Thus, whatever is the mode of action of 2,6-xylidine carcinogenicity in rodents, it has proven impossible to detect mutagenic effects in Ames tests with numerous variations of metabolic conditions, or even using acetyltransferase overexpressing strains of bacteria.
    MeSH term(s) Aniline Compounds/metabolism ; Aniline Compounds/toxicity ; Animals ; Cytochrome P-450 Enzyme System/metabolism ; Escherichia coli/drug effects ; Escherichia coli/genetics ; Humans ; Hydroxylamines/metabolism ; Hydroxylamines/toxicity ; Liver/metabolism ; Mutagenicity Tests ; Rats ; Recombinant Proteins/metabolism ; Salmonella typhimurium/drug effects ; Salmonella typhimurium/genetics
    Chemical Substances Aniline Compounds ; Hydroxylamines ; Recombinant Proteins ; 2,6-xylidine (4FT62OX08D) ; Cytochrome P-450 Enzyme System (9035-51-2) ; 2,4-dimethylphenylhydroxylamine (J5RJO46I1F)
    Language English
    Publishing date 2012-02
    Publishing country Netherlands
    Document type Journal Article
    ZDB-ID 604672-1
    ISSN 1096-0295 ; 0273-2300
    ISSN (online) 1096-0295
    ISSN 0273-2300
    DOI 10.1016/j.yrtph.2011.08.010
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1711: Show issues Location:
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  5. Article ; Online: Structure-Based Design and Preclinical Characterization of Selective and Orally Bioavailable Factor XIa Inhibitors: Demonstrating the Power of an Integrated S1 Protease Family Approach.

    Lorthiois, Edwige / Roache, James / Barnes-Seeman, David / Altmann, Eva / Hassiepen, Ulrich / Turner, Gordon / Duvadie, Rohit / Hornak, Viktor / Karki, Rajeshri G / Schiering, Nikolaus / Weihofen, Wilhelm A / Perruccio, Francesca / Calhoun, Amy / Fazal, Tanzina / Dedic, Darija / Durand, Corinne / Dussauge, Solene / Fettis, Kamal / Tritsch, Fabien /
    Dentel, Celine / Druet, Adelaide / Liu, Donglei / Kirman, Louise / Lachal, Julie / Namoto, Kenji / Bevan, Douglas / Mo, Rose / Monnet, Gabriela / Muller, Lionel / Zessis, Richard / Huang, Xueming / Lindsley, Loren / Currie, Treeve / Chiu, Yu-Hsin / Fridrich, Cary / Delgado, Peter / Wang, Shuangxi / Hollis-Symynkywicz, Micah / Berghausen, Joerg / Williams, Eric / Liu, Hong / Liang, Guiqing / Kim, Hyungchul / Hoffmann, Peter / Hein, Andreas / Ramage, Paul / D'Arcy, Allan / Harlfinger, Stefanie / Renatus, Martin / Ruedisser, Simon / Feldman, David / Elliott, Jason / Sedrani, Richard / Maibaum, Juergen / Adams, Christopher M

    Journal of medicinal chemistry

    2020  Volume 63, Issue 15, Page(s) 8088–8113

    Abstract: The serine protease factor XI (FXI) is a prominent drug target as it holds promise to deliver efficacious anticoagulation without an enhanced risk of major bleeds. Several efforts have been described targeting the active form of the enzyme, FXIa. Herein, ...

    Abstract The serine protease factor XI (FXI) is a prominent drug target as it holds promise to deliver efficacious anticoagulation without an enhanced risk of major bleeds. Several efforts have been described targeting the active form of the enzyme, FXIa. Herein, we disclose our efforts to identify potent, selective, and orally bioavailable inhibitors of FXIa. Compound
    MeSH term(s) Administration, Oral ; Amino Acid Sequence ; Animals ; Biological Availability ; Dogs ; Drug Evaluation, Preclinical/methods ; Factor XIa/antagonists & inhibitors ; Factor XIa/genetics ; Factor Xa Inhibitors/administration & dosage ; Factor Xa Inhibitors/chemistry ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Rats ; Rats, Sprague-Dawley ; Structure-Activity Relationship
    Chemical Substances Factor Xa Inhibitors ; Factor XIa (EC 3.4.21.27)
    Language English
    Publishing date 2020-07-21
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 218133-2
    ISSN 1520-4804 ; 0022-2623
    ISSN (online) 1520-4804
    ISSN 0022-2623
    DOI 10.1021/acs.jmedchem.0c00279
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  6. Article: Toxicokinetics of acrylamide in humans after ingestion of a defined dose in a test meal to improve risk assessment for acrylamide carcinogenicity.

    Fuhr, Uwe / Boettcher, Melanie I / Kinzig-Schippers, Martina / Weyer, Alexandra / Jetter, Alexander / Lazar, Andreas / Taubert, Dirk / Tomalik-Scharte, Dorota / Pournara, Panagiota / Jakob, Verena / Harlfinger, Stefanie / Klaassen, Tobias / Berkessel, Albrecht / Angerer, Jürgen / Sörgel, Fritz / Schömig, Edgar

    Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology

    2006  Volume 15, Issue 2, Page(s) 266–271

    Abstract: High amounts of acrylamide in some foods result in an estimated daily mean intake of 50 microg for a western style diet. Animal studies have shown the carcinogenicity of acrylamide upon oral exposure. However, only sparse human toxicokinetic data is ... ...

    Abstract High amounts of acrylamide in some foods result in an estimated daily mean intake of 50 microg for a western style diet. Animal studies have shown the carcinogenicity of acrylamide upon oral exposure. However, only sparse human toxicokinetic data is available for acrylamide, which is needed for the extrapolation of human cancer risk from animal data. We evaluated the toxicokinetics of acrylamide in six young healthy volunteers after the consumption of a meal containing 0.94 mg of acrylamide. Urine was collected up to 72 hours thereafter. Unchanged acrylamide, its mercapturic acid metabolite N-acetyl-S-(2-carbamoylethyl)cysteine (AAMA), its epoxy derivative glycidamide, and the respective metabolite of glycidamide, N-acetyl-S-(2-hydroxy-2-carbamoylethyl)cysteine (GAMA), were quantified in the urine by liquid chromatography-mass spectrometry. Toxicokinetic variables were obtained by noncompartmental methods. Overall, 60.3 +/- 11.2% of the dose was recovered in the urine. Although no glycidamide was found, unchanged acrylamide, AAMA, and GAMA accounted for urinary excretion of (mean +/- SD) 4.4 +/- 1.5%, 50.0 +/- 9.4%, and 5.9 +/- 1.2% of the dose, respectively. Apparent terminal elimination half-lives for the substances were 2.4 +/- 0.4, 17.4 +/- 3.9, and 25.1 +/- 6.4 hours. The ratio of GAMA/AAMA amounts excreted was 0.12 +/- 0.02. In conclusion, most of the acrylamide ingested with food is absorbed in humans. Conjugation with glutathione exceeds the formation of the reactive metabolite glycidamide. The data suggests an at least 2-fold and 4-fold lower relative internal exposure for glycidamide from dietary acrylamide in humans compared with rats or mice, respectively. This should be considered for quantitative cancer risk assessment.
    MeSH term(s) Absorption ; Acrylamide/administration & dosage ; Acrylamide/pharmacokinetics ; Acrylamide/toxicity ; Adult ; Animals ; Carcinogens/pharmacokinetics ; Cooking/methods ; Dietary Fats ; Epoxy Compounds/urine ; Female ; Half-Life ; Humans ; Male ; Risk Assessment ; Solanum tuberosum/chemistry ; Species Specificity ; Time Factors
    Chemical Substances Carcinogens ; Dietary Fats ; Epoxy Compounds ; Acrylamide (20R035KLCI) ; glycidamide (6G5ELX5XYN)
    Language English
    Publishing date 2006-02
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1153420-5
    ISSN 1055-9965
    ISSN 1055-9965
    DOI 10.1158/1055-9965.EPI-05-0647
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 3693: Show issues Location:
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