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Liquid chromatography–tandem mass spectrometry metabolic profiling of nazartinib reveals the formation of unexpected reactive metabolites

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...

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Autores principales: Abdelhameed, Ali S., Attwa, Mohamed W., Kadi, Adnan A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Royal Society 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6731747/
https://www.ncbi.nlm.nih.gov/pubmed/31598253
http://dx.doi.org/10.1098/rsos.190852
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author Abdelhameed, Ali S.
Attwa, Mohamed W.
Kadi, Adnan A.
author_facet Abdelhameed, Ali S.
Attwa, Mohamed W.
Kadi, Adnan A.
author_sort Abdelhameed, Ali S.
collection PubMed
description 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.
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spelling pubmed-67317472019-10-09 Liquid chromatography–tandem mass spectrometry metabolic profiling of nazartinib reveals the formation of unexpected reactive metabolites Abdelhameed, Ali S. Attwa, Mohamed W. Kadi, Adnan A. R Soc Open Sci Chemistry 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. The Royal Society 2019-08-14 /pmc/articles/PMC6731747/ /pubmed/31598253 http://dx.doi.org/10.1098/rsos.190852 Text en © 2019 The Authors. http://creativecommons.org/licenses/by/4.0/ Published by the Royal Society under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/4.0/, which permits unrestricted use, provided the original author and source are credited.
spellingShingle Chemistry
Abdelhameed, Ali S.
Attwa, Mohamed W.
Kadi, Adnan A.
Liquid chromatography–tandem mass spectrometry metabolic profiling of nazartinib reveals the formation of unexpected reactive metabolites
title Liquid chromatography–tandem mass spectrometry metabolic profiling of nazartinib reveals the formation of unexpected reactive metabolites
title_full Liquid chromatography–tandem mass spectrometry metabolic profiling of nazartinib reveals the formation of unexpected reactive metabolites
title_fullStr Liquid chromatography–tandem mass spectrometry metabolic profiling of nazartinib reveals the formation of unexpected reactive metabolites
title_full_unstemmed Liquid chromatography–tandem mass spectrometry metabolic profiling of nazartinib reveals the formation of unexpected reactive metabolites
title_short Liquid chromatography–tandem mass spectrometry metabolic profiling of nazartinib reveals the formation of unexpected reactive metabolites
title_sort liquid chromatography–tandem mass spectrometry metabolic profiling of nazartinib reveals the formation of unexpected reactive metabolites
topic Chemistry
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6731747/
https://www.ncbi.nlm.nih.gov/pubmed/31598253
http://dx.doi.org/10.1098/rsos.190852
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