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

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Title
Metabolite profiling and characterization of LW6, a novel HIF-1α inhibitor, as an antitumor drug candidate in mice
Author(s)
K Lee; J Y Lee; K Lee; Cho-Rok JungMin Ju Kim; J A Kim; D G Yoo; E J Shin; S J Oh
Bibliographic Citation
Molecules, vol. 26, no. 7, pp. 1951-1951
Publication Year
2021
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.
Keyword
LW6Hypoxia-inducible factor-1αMetabolite identificationHybrid triple quadrupolelinear ion trap mass spectrometerPredictive multiple reaction monitoring-information dependent acquisition-enhanced product ion
ISSN
1420-3049
Publisher
MDPI
DOI
http://dx.doi.org/10.3390/molecules26071951
Type
Article
Appears in Collections:
Division of Research on National Challenges > Stem Cell Convergenece Research Center > 1. Journal Articles
Ochang Branch Institute > Division of National Bio-Infrastructure > Laboratory Animal Resource & Research Center > 1. Journal Articles
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