FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W3035996831> ?p ?o ?g. }

• W3035996831 endingPage "299" @default.
• W3035996831 startingPage "281" @default.
• W3035996831 abstract "Abstract Drug-induced liver injury is a major reason for drug candidate attrition from development, denied commercialization, market withdrawal, and restricted prescribing of pharmaceuticals. The metabolic bioactivation of drugs to chemically reactive metabolites (CRMs) contribute to liver-associated adverse drug reactions in humans that often goes undetected in conventional animal toxicology studies. A challenge for pharmaceutical drug discovery has been reliably selecting drug candidates with a low liability of forming CRM and reduced drug-induced liver injury potential, at projected therapeutic doses, without falsely restricting the development of safe drugs. We have developed an in vivo rat liver transcriptional signature biomarker reflecting the cellular response to drug bioactivation. Measurement of transcriptional activation of integrated nuclear factor erythroid 2-related factor 2 (NRF2)/Kelch-like ECH-associated protein 1 (KEAP1) electrophilic stress, and nuclear factor erythroid 2-related factor 1 (NRF1) proteasomal endoplasmic reticulum (ER) stress responses, is described for discerning estimated clinical doses of drugs with potential for bioactivation-mediated hepatotoxicity. The approach was established using well benchmarked CRM forming test agents from our company. This was subsequently tested using curated lists of commercial drugs and internal compounds, anchored in the clinical experience with human hepatotoxicity, while agnostic to mechanism. Based on results with 116 compounds in short-term rat studies, with consideration of the maximum recommended daily clinical dose, this CRM mechanism-based approach yielded 32% sensitivity and 92% specificity for discriminating safe from hepatotoxic drugs. The approach adds new information for guiding early candidate selection and informs structure activity relationships (SAR) thus enabling lead optimization and mechanistic problem solving. Additional refinement of the model is ongoing. Case examples are provided describing the strengths and limitations of the approach." @default.
• W3035996831 created "2020-06-25" @default.
• W3035996831 creator A5005293244 @default.
• W3035996831 creator A5009394304 @default.
• W3035996831 creator A5012608546 @default.
• W3035996831 creator A5013012980 @default.
• W3035996831 creator A5014194912 @default.
• W3035996831 creator A5028370411 @default.
• W3035996831 creator A5028563496 @default.
• W3035996831 creator A5028617710 @default.
• W3035996831 creator A5038411131 @default.
• W3035996831 creator A5040361202 @default.
• W3035996831 creator A5046913717 @default.
• W3035996831 creator A5057492249 @default.
• W3035996831 creator A5062300741 @default.
• W3035996831 creator A5064222916 @default.
• W3035996831 creator A5065822951 @default.
• W3035996831 creator A5072472333 @default.
• W3035996831 creator A5072723508 @default.
• W3035996831 creator A5089749434 @default.
• W3035996831 date "2020-06-19" @default.
• W3035996831 modified "2023-10-01" @default.
• W3035996831 title "Application of a Rat Liver Drug Bioactivation Transcriptional Response Assay Early in Drug Development That Informs Chemically Reactive Metabolite Formation and Potential for Drug-induced Liver Injury" @default.
• W3035996831 cites W1968195910 @default.
• W3035996831 cites W1987144475 @default.
• W3035996831 cites W1996935441 @default.
• W3035996831 cites W1999587831 @default.
• W3035996831 cites W2017061029 @default.
• W3035996831 cites W2036392083 @default.
• W3035996831 cites W2043472568 @default.
• W3035996831 cites W2048700223 @default.
• W3035996831 cites W2064798207 @default.
• W3035996831 cites W2075221169 @default.
• W3035996831 cites W2098159917 @default.
• W3035996831 cites W2099536383 @default.
• W3035996831 cites W2101016189 @default.
• W3035996831 cites W2104209550 @default.
• W3035996831 cites W2108845723 @default.
• W3035996831 cites W2108941700 @default.
• W3035996831 cites W2109972881 @default.
• W3035996831 cites W2121856209 @default.
• W3035996831 cites W2140639850 @default.
• W3035996831 cites W2146402650 @default.
• W3035996831 cites W2146883699 @default.
• W3035996831 cites W2150892054 @default.
• W3035996831 cites W2161569589 @default.
• W3035996831 cites W2218204925 @default.
• W3035996831 cites W2415186660 @default.
• W3035996831 cites W2478986464 @default.
• W3035996831 cites W2570155983 @default.
• W3035996831 cites W2886008099 @default.
• W3035996831 cites W2891677948 @default.
• W3035996831 cites W2941010478 @default.
• W3035996831 cites W2943954271 @default.
• W3035996831 cites W3009527553 @default.
• W3035996831 cites W3036869301 @default.
• W3035996831 cites W2954576340 @default.
• W3035996831 doi "https://doi.org/10.1093/toxsci/kfaa088" @default.
• W3035996831 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/7553701" @default.
• W3035996831 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/32559301" @default.
• W3035996831 hasPublicationYear "2020" @default.
• W3035996831 type Work @default.
• W3035996831 sameAs 3035996831 @default.
• W3035996831 citedByCount "22" @default.
• W3035996831 countsByYear W30359968312020 @default.
• W3035996831 countsByYear W30359968312021 @default.
• W3035996831 countsByYear W30359968312022 @default.
• W3035996831 countsByYear W30359968312023 @default.
• W3035996831 crossrefType "journal-article" @default.
• W3035996831 hasAuthorship W3035996831A5005293244 @default.
• W3035996831 hasAuthorship W3035996831A5009394304 @default.
• W3035996831 hasAuthorship W3035996831A5012608546 @default.
• W3035996831 hasAuthorship W3035996831A5013012980 @default.
• W3035996831 hasAuthorship W3035996831A5014194912 @default.
• W3035996831 hasAuthorship W3035996831A5028370411 @default.
• W3035996831 hasAuthorship W3035996831A5028563496 @default.
• W3035996831 hasAuthorship W3035996831A5028617710 @default.
• W3035996831 hasAuthorship W3035996831A5038411131 @default.
• W3035996831 hasAuthorship W3035996831A5040361202 @default.
• W3035996831 hasAuthorship W3035996831A5046913717 @default.
• W3035996831 hasAuthorship W3035996831A5057492249 @default.
• W3035996831 hasAuthorship W3035996831A5062300741 @default.
• W3035996831 hasAuthorship W3035996831A5064222916 @default.
• W3035996831 hasAuthorship W3035996831A5065822951 @default.
• W3035996831 hasAuthorship W3035996831A5072472333 @default.
• W3035996831 hasAuthorship W3035996831A5072723508 @default.
• W3035996831 hasAuthorship W3035996831A5089749434 @default.
• W3035996831 hasBestOaLocation W30359968311 @default.
• W3035996831 hasConcept C104317684 @default.
• W3035996831 hasConcept C150194340 @default.
• W3035996831 hasConcept C150903083 @default.
• W3035996831 hasConcept C185592680 @default.
• W3035996831 hasConcept C207001950 @default.
• W3035996831 hasConcept C2776637226 @default.
• W3035996831 hasConcept C2777477808 @default.
• W3035996831 hasConcept C2780035454 @default.
• W3035996831 hasConcept C55493867 @default.
• W3035996831 hasConcept C64903051 @default.

• next