Utilization of human nuclear receptors as an early counter screen for off-target activity: a case study with a compendium of 615 known drugs
Off-target effects of drugs on nuclear hormone receptors (NHRs) may result in adverse effects in multiple organs/physiological processes. Reliable assessments of the NHR activities for drug candidates are therefore crucial for drug development. However, the highly permissive structures of NHRs for v...
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Published in | Toxicological sciences Vol. 145; no. 2; pp. 283 - 295 |
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Main Authors | , , , , , , , , , , |
Format | Journal Article |
Language | English |
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United States
01.06.2015
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Abstract | Off-target effects of drugs on nuclear hormone receptors (NHRs) may result in adverse effects in multiple organs/physiological processes. Reliable assessments of the NHR activities for drug candidates are therefore crucial for drug development. However, the highly permissive structures of NHRs for vastly different ligands make it challenging to predict interactions by examining the chemical structures of the ligands. Here, we report a detailed investigation on the agonistic and antagonistic activities of 615 known drugs or drug candidates against a panel of 6 NHRs: androgen, progesterone, estrogen α/β, and thyroid hormone α/β receptors. Our study revealed that 4.7 and 12.4% compounds have agonistic and antagonistic activities, respectively, against this panel of NHRs. Nonetheless, potent, unintended NHR hits are relatively rare among the known drugs, indicating that such interactions are perhaps not tolerated during drug development. However, we uncovered examples of compounds that unintentionally agonize or antagonize NHRs. In addition, a number of compounds showed multi-NHR activities, suggesting that the cross-talk between multiple NHRs co-operate to elicit in vivo effects. These data highlight the merits of counter screening drug candidate against NHRs during drug discovery/development. |
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AbstractList | Off-target effects of drugs on nuclear hormone receptors (NHRs) may result in adverse effects in multiple organs/physiological processes. Reliable assessments of the NHR activities for drug candidates are therefore crucial for drug development. However, the highly permissive structures of NHRs for vastly different ligands make it challenging to predict interactions by examining the chemical structures of the ligands. Here, we report a detailed investigation on the agonistic and antagonistic activities of 615 known drugs or drug candidates against a panel of 6 NHRs: androgen, progesterone, estrogen α/β, and thyroid hormone α/β receptors. Our study revealed that 4.7 and 12.4% compounds have agonistic and antagonistic activities, respectively, against this panel of NHRs. Nonetheless, potent, unintended NHR hits are relatively rare among the known drugs, indicating that such interactions are perhaps not tolerated during drug development. However, we uncovered examples of compounds that unintentionally agonize or antagonize NHRs. In addition, a number of compounds showed multi-NHR activities, suggesting that the cross-talk between multiple NHRs co-operate to elicit in vivo effects. These data highlight the merits of counter screening drug candidate against NHRs during drug discovery/development. |
Author | Strauch, Simone Nioi, Paul Fan, Fan Afshari, Cynthia A Dunn, 2nd, Robert T Chen, Yuan Munzli, Anke Hamadeh, Hisham Hu, Rong Weikl, Kerstin Schwandner, Ralf |
Author_xml | – sequence: 1 givenname: Fan surname: Fan fullname: Fan, Fan organization: Amgen Inc., Comparative Biology and Safety Sciences, Department of Discovery Toxicology, Thousand Oaks, California 91320 and Amgen Research GmbH, 93053 Regensburg, Germany – sequence: 2 givenname: Rong surname: Hu fullname: Hu, Rong organization: Amgen Inc., Comparative Biology and Safety Sciences, Department of Discovery Toxicology, Thousand Oaks, California 91320 and Amgen Research GmbH, 93053 Regensburg, Germany – sequence: 3 givenname: Anke surname: Munzli fullname: Munzli, Anke organization: Amgen Inc., Comparative Biology and Safety Sciences, Department of Discovery Toxicology, Thousand Oaks, California 91320 and Amgen Research GmbH, 93053 Regensburg, Germany – sequence: 4 givenname: Yuan surname: Chen fullname: Chen, Yuan organization: Amgen Inc., Comparative Biology and Safety Sciences, Department of Discovery Toxicology, Thousand Oaks, California 91320 and Amgen Research GmbH, 93053 Regensburg, Germany – sequence: 5 givenname: Robert T surname: Dunn, 2nd fullname: Dunn, 2nd, Robert T organization: Amgen Inc., Comparative Biology and Safety Sciences, Department of Discovery Toxicology, Thousand Oaks, California 91320 and Amgen Research GmbH, 93053 Regensburg, Germany – sequence: 6 givenname: Kerstin surname: Weikl fullname: Weikl, Kerstin organization: Amgen Inc., Comparative Biology and Safety Sciences, Department of Discovery Toxicology, Thousand Oaks, California 91320 and Amgen Research GmbH, 93053 Regensburg, Germany – sequence: 7 givenname: Simone surname: Strauch fullname: Strauch, Simone organization: Amgen Inc., Comparative Biology and Safety Sciences, Department of Discovery Toxicology, Thousand Oaks, California 91320 and Amgen Research GmbH, 93053 Regensburg, Germany – sequence: 8 givenname: Ralf surname: Schwandner fullname: Schwandner, Ralf organization: Amgen Inc., Comparative Biology and Safety Sciences, Department of Discovery Toxicology, Thousand Oaks, California 91320 and Amgen Research GmbH, 93053 Regensburg, Germany – sequence: 9 givenname: Cynthia A surname: Afshari fullname: Afshari, Cynthia A organization: Amgen Inc., Comparative Biology and Safety Sciences, Department of Discovery Toxicology, Thousand Oaks, California 91320 and Amgen Research GmbH, 93053 Regensburg, Germany – sequence: 10 givenname: Hisham surname: Hamadeh fullname: Hamadeh, Hisham organization: Amgen Inc., Comparative Biology and Safety Sciences, Department of Discovery Toxicology, Thousand Oaks, California 91320 and Amgen Research GmbH, 93053 Regensburg, Germany – sequence: 11 givenname: Paul surname: Nioi fullname: Nioi, Paul email: pnioi@amgen.com organization: Amgen Inc., Comparative Biology and Safety Sciences, Department of Discovery Toxicology, Thousand Oaks, California 91320 and Amgen Research GmbH, 93053 Regensburg, Germany pnioi@amgen.com |
BackLink | https://www.ncbi.nlm.nih.gov/pubmed/25752796$$D View this record in MEDLINE/PubMed |
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Keywords | androgen receptor in vitro profiling estrogen receptor hazard identification thyroid receptor nuclear hormone receptor progesterone receptor |
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Snippet | Off-target effects of drugs on nuclear hormone receptors (NHRs) may result in adverse effects in multiple organs/physiological processes. Reliable assessments... |
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SubjectTerms | Binding Sites Binding, Competitive Cell Line Drug Discovery - methods Drug-Related Side Effects and Adverse Reactions - etiology Drug-Related Side Effects and Adverse Reactions - metabolism Drug-Related Side Effects and Adverse Reactions - prevention & control Endocrine Disruptors - chemistry Endocrine Disruptors - toxicity Genes, Reporter Hormone Antagonists - chemistry Hormone Antagonists - toxicity Humans Ligands Models, Molecular Protein Binding Protein Conformation Receptors, Cytoplasmic and Nuclear - chemistry Receptors, Cytoplasmic and Nuclear - drug effects Receptors, Cytoplasmic and Nuclear - genetics Receptors, Cytoplasmic and Nuclear - metabolism Risk Assessment Spectrometry, Fluorescence Transfection |
Title | Utilization of human nuclear receptors as an early counter screen for off-target activity: a case study with a compendium of 615 known drugs |
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