Data from: Liquid chromatography-tandem mass spectrometry metabolic profiling of nazartinib reveals the formation of unexpected reactive metabolites
Data files
Jul 24, 2019 version files 3.33 MB
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NZB HLMs 481.xls
369.66 KB
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NZB HLMs 495.xls
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NZB HLMs 509a.xls
369.66 KB
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NZB HLMs 509b.xls
369.66 KB
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NZB HLMs 509c.xls
369.66 KB
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NZB HLMs 511a.xls
369.66 KB
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NZB HLMs 511b.xls
369.66 KB
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NZB HLMs KCN 506.xls
369.66 KB
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NZB HLMs KCN 520.xls
369.66 KB
Jul 24, 2019 version files 6.65 MB
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NZB HLMs 481.xls
369.66 KB
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NZB HLMs 495.xls
369.66 KB
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NZB HLMs 509a.xls
369.66 KB
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NZB HLMs 509b.xls
369.66 KB
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NZB HLMs 509c.xls
369.66 KB
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NZB HLMs 511a.xls
369.66 KB
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NZB HLMs 511b.xls
369.66 KB
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NZB HLMs KCN 506.xls
369.66 KB
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NZB HLMs KCN 520.xls
369.66 KB
Abstract
Nazartinib (EGF816, NZB) is a promising third-generation human epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor. This novel irreversible mutant-selective EGFR inhibitor targets EGFR containing both the resistance mutation (T790M) and the activating mutations (L858R and Del19), while it does not affect wild-type EGFR. However, the metabolic pathway and bioactivation mechanisms of NZB are still unexplored. Thus, using liquid chromatography-tandem mass spectrometry, we screened for products of NZB metabolism formed in vitro by human liver microsomal preparations and investigated the formation of reactive intermediates using potassium cyanide as a nucleophile trap. Unexpectedly, the azepane ring was not bioactivated. Instead, the carbon atom between the aliphatic linear tertiary amine and electron-withdrawing system (butenoyl amide group) was bioactivated, generating iminium intermediates as reactive species. Six NZB phase I metabolites, formed by hydroxylation, oxidation, and N-demethylation, were characterized. Moreover, two reactive iminium ions were characterized and their corresponding bioactivation mechanisms were proposed. Based on our results, we speculate that bioactivation of NZB can be blocked by small sterically hindering groups, isosteric replacement, or a spacer. This approach might reduce the toxicity of NZB by avoiding the generation of reactive species.