Affiliation:
1. Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, PO Box 2457, Riyadh 11451, Kingdom of Saudi Arabia
2. Students’ University Hospital, Mansoura University, Mansoura 35516, Egypt
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.
Funder
Deanship of Scientific Research at King Saud University
Cited by
2 articles.
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