Výsledky vyhledávání - "Konstantine W. Skordos"

The Conduct of in Vitro Studies to Address Time-Dependent Inhibition of Drug-Metabolizing Enzymes: A Perspective of the Pharmaceutical Research and Manufacturers of America

Autor: Robert Van Horn, Scott W. Grimm, George Tonn, Kah-Hiing John Ling, R. Scott Obach, Chuang Lu, Steven D. Hall, Heng-Keang Lim, Tian J. Yang, Heidi J. Einolf, Konstantine W. Skordos, Amin A. Nomeir, Y. Nancy Wong, Kan He, Eleanore Seibert, Regina W. Wang

Publikováno v: Drug Metabolism and Disposition. 37:1355-1370

Time-dependent inhibition (TDI) of cytochrome P450 (P450) enzymes caused by new molecular entities (NMEs) is of concern because such compounds can be responsible for clinically relevant drug-drug interactions (DDI). Although the biochemistry underlyi

Externí odkaz: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::72b1477d84a7485059dd439f96511773
https://doi.org/10.1124/dmd.109.026716

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Single Mutations Change CYP2F3 From a Dehydrogenase of 3-Methylindole to an Oxygenase

Autor: Hao Sun, Konstantine W. Skordos, Christopher A. Reilly, Clifton Hall, Jaya S. Kartha, Eric F. Johnson, LaHoma M. Easterwood, Garold S. Yost

Publikováno v: Biochemistry. 47:9756-9770

Pulmonary cytochrome P450 2F3 (CYP2F3) catalyzes the dehydrogenation of the pneumotoxin 3-methylindole (3MI) to an electrophilic intermediate, 3-methyleneindolenine, which is responsible for the toxicity of the parent compound. Members of the CYP2F s

Externí odkaz: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::d528ff7427c55ca5cf66c52ca1b5aa89
https://doi.org/10.1021/bi8005658

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3-Methylindole-Induced Toxicity to Human Bronchial Epithelial Cell Lines

Autor: Williams K. Nichols, Garold S. Yost, Rashmi Mehta, Scott W. Burchiel, Tamara Minko, Konstantine W. Skordos, Andrea M. A. Pfeifer, Katherine Macé, Brian A. Carr

Publikováno v: Toxicological Sciences. 71:229-236

Transfected BEAS-2B cells that express different cytochrome P450 enzymes were used to assess whether human bronchial epithelial cell lines are target cells for 3-methylindole (3MI)-induced damage. Four different transfected BEAS-2B lines overexpressi

Externí odkaz: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::ba2996d5d8bbe1a7b35dfc1b67ec7192
https://doi.org/10.1093/toxsci/71.2.229

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The metabolic drug-drug interaction profile of Dabrafenib: in vitro investigations and quantitative extrapolation of the P450-mediated DDI risk

Autor: Sarah K. Lawrence, Chester L. Bowen, Konstantine W. Skordos, Lauren E. Richards-Peterson, Dung Nguyen

Publikováno v: Drug metabolism and disposition: the biological fate of chemicals. 42(7)

Dabrafenib is a potent ATP-competitive inhibitor for the V600 mutant b-rapidly accelerated fibrosarcoma (b-raf) kinase currently approved in the United States for the treatment of metastatic melanoma. Studies were conducted in human liver microsomes,

Externí odkaz: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::ea5b4c44beb148fb4b9535d0ef7382ce
https://pubmed.ncbi.nlm.nih.gov/24748562

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Thioether Adducts of a New Imine Reactive Intermediate of the Pneumotoxin 3-Methylindole

Autor: Garold S. Yost, Konstantine W. Skordos, John D. Laycock

Publikováno v: Chemical Research in Toxicology. 11:1326-1331

Cytochrome P450 enzymes can potentially oxygenate 3-methylindole to form 2,3-epoxy-3-methylindoline which could rearrange to the stable metabolite 3-methyloxindole or open to form 3-hydroxy-3-methylindolenine, a putative electrophilic imine. The purp

Externí odkaz: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::64885e23a9bc34c383fed41e00a20536
https://doi.org/10.1021/tx9801209

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Inhibition of Polo-like kinase 1 prevents the growth of metastatic breast cancer cells in the brain

Publikováno v: Clin Exp Metastasis

Few therapeutic strategies exist for the treatment of metastatic tumor cells in the brain because the blood–brain barrier (BBB) limits drug access. Thus the identification of molecular targets and accompanying BBB permeable drugs will significantly

Externí odkaz: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::af73e7bdd417b4e8e0d5e722f2171388
https://europepmc.org/articles/PMC7416514/

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Utilizing drug-drug interaction prediction tools during drug development: enhanced decision making based on clinical risk

Autor: Konstantine W. Skordos, Grant T. Generaux, Christopher MacLauchlin, Nicoletta Pons, Jackie C. Bloomer, Carole Shardlow

Publikováno v: Drug metabolism and disposition: the biological fate of chemicals. 39(11)

Several reports in the literature present the utility and value of in vitro drug-metabolizing enzyme inhibition data to predict in vivo drug-drug interactions in humans. A retrospective analysis has been conducted for 26 GlaxoSmithKline (GSK) drugs a

Externí odkaz: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::fa4718e3bc95e4ef9a40bb81551168c2
https://pubmed.ncbi.nlm.nih.gov/21832001

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Zafirlukast metabolism by cytochrome P450 3A4 produces an electrophilic alpha,beta-unsaturated iminium species that results in the selective mechanism-based inactivation of the enzyme

Autor: Garold S. Yost, Kelem Kassahun, Thomas A. Baillie, Konstantine W. Skordos, Donald Slaughter, George A. Doss, Ian McIntosh

Publikováno v: Chemical research in toxicology. 18(9)

Zafirlukast is a leukotriene antagonist indicated for the treatment of mild to moderate asthma, but the drug has been associated with occasional idiosyncratic hepatotoxicity. Structurally, zafirlukast is similar to 3-methylindole because it contains

Externí odkaz: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::bb6acec64fd36df1dc0d14eda3e39677
https://pubmed.ncbi.nlm.nih.gov/16167835

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Evidence supporting the formation of 2,3-epoxy-3-methylindoline: a reactive intermediate of the pneumotoxin 3-methylindole

Autor: Konstantine W. Skordos, Gary L. Skiles, Garold S. Yost, John D. Laycock, Diane L. Lanza

Publikováno v: Chemical research in toxicology. 11(7)

The existence of a cytochrome P450-dependent 2,3-epoxide of the potent pneumotoxin 3-methylindole was indirectly confirmed using stable isotope techniques and mass spectrometry. Determination of hydride shift and incorporation of labeled oxygen in 3-

Externí odkaz: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::88989d573a7a448c29de0b144fa79a80
https://pubmed.ncbi.nlm.nih.gov/9671536

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Abstract 1752: A phase I/IIa, first time in human, open-label dose-escalation study of GSK2636771 in subjects with advanced solid tumors with PTEN deficiency

Autor: Monica Motwani, Samuel C. Blackman, Joel Greshock, Mary Ann Hardwicke, Lori T Roadcap, Benjamin B. Suttle, Konstantine W. Skordos, Richard Wooster, Shelby D. Gainer

Publikováno v: Cancer Research. 72:1752-1752

Background: The phosphoinositide 3-kinase (PI3K) pathway is among the most commonly mutated pathways in human cancer. The majority of first-generation PI3K inhibitors currently in clinical trials inhibit multiple PI3K isoforms. The PIK3CB gene encode

Externí odkaz: https://explore.openaire.eu/search/publication?articleId=doi_________::30e54aaff68373210daa450e5002c30f
https://doi.org/10.1158/1538-7445.am2012-1752

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