Metabolite profiling and characterization of LW6, a novel HIF-1α inhibitor, as an antitumor drug candidate in mice

Kiho Lee, Ji Yoon Lee, Kyeong Lee, Cho Rock Jung, Min Ju Kim, Jung Ah Kim, Dong Gu Yoo, Eun Jin Shin, Soo Jin Oh

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

A novel HIF (hypoxia-inducible factor)-1α inhibitor, the (aryloxyacetylamino)benzoic acid derivative LW6, is an anticancer agent that inhibits the accumulation of HIF-1α. The aim of this study was to characterize and determine the structures of the metabolites of LW6 in ICR mice. Metabolite identification was performed using a predictive multiple reaction monitoring-information dependent acquisition-enhanced product ion (pMRM-IDA-EPI) method in negative ion mode on a hybrid triple quadrupole-linear ion trap mass spectrometer (QTRAP). A total of 12 metabolites were characterized based on their MS/MS spectra, and the retention times were compared with those of the parent compound. The metabolites were divided into five structural classes based on biotransformation reactions: amide hydrolysis, ester hydrolysis, mono-oxidation, glucuronidation, and a combination of these reactions. From this study, 2-(4-((3r,5r,7r)-adamantan-1-yl)phenoxy)acetic acid (APA, M7), the metabolite produced via amide hydrolysis, was found to be a major circulating metabolite of LW6 in mice. The results of this study can be used to improve the pharmacokinetic profile by lowering the clearance and increasing the exposure relative to LW6.

Original languageEnglish
Article number1951
JournalMolecules
Volume26
Issue number7
DOIs
StatePublished - 1 Apr 2021

Keywords

  • Hybrid triple quadrupolelinear ion trap mass spectrometer
  • Hypoxia-inducible factor-1α
  • LW6
  • Metabolite identification
  • Predictive multiple reaction monitoring-information dependent acquisition-enhanced production

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